Mass Effect has Garrus Vakarian and male Shepard, as well as Tali'Zorah and female Shepard. And in the truest expression of this trope, they are both romancable in the second and third games when Shepard is the opposite sex. The fact that they hook up with each other if you don't, says something about the trio as a whole.
Sam: Want to go in the tunnel of love? Max: Yippee!!
When Sam and Max are separated in "Culture Shock", Sam actually starts to hallucinate from withdrawal.
Lampshaded in "Abe Lincoln Must Die!", where according to Sybil's "compatibility test", their soul mates are each other.
In "Chariots of the Dogs", a woman develops a crush on Max, and when Sam objects (because the woman in question is Bosco's mother, and that would cause a Time Paradox), she seems to assume he's gay, and "wants to keep [Max] all for himself".
In "What's New, Beelzebub?", when Sam tells Max that Demon Peepers claims to be his new best friend, Max rips out Demon Peepers' kidneys.
But probably the most iconic example is in "They Stole Max's Brain!" when Sam, believing Max has been murdered, goes in a Roaring Rampage of Revenge, stylized as a film Noir hard-boiled detective mystery, using Jack Bauer Interrogation Technique in every suspect to figure out, well, who stole Max's Brain. He even threatens friends at Gun Point to obtain information! He gets a lot better when he know Max is okay though.
This is highlighted tear-jerkingly well in "The City That Dares Not Sleep" when Max does die. Instead of going on a rampage, however, Sam simply... loses hope. As the credits roll, we see Sam walking dejectedly through the streets of New York. Luckily, a Max from a universe where Sam dies appears. The two seem to agree to use the other as a Replacement Goldfish. They then go out to stop more crime.
If you think the video games are Ho Yay suggestive, check out the animated series, and it was for kids.
Apparently Kenshi has a thing for ninjas, as seen in Mortal Kombat: Deception with his interactions with both Ermac and Sub-Zero. Then there's his latest stint with Scorpion from Mortal Kombat X, to the point where they basically share Takeda - son of Kenshi, trained by Scorpion.
Uncharted Nathan Drake and Victor Sullivan seem to fit this pretty well, and Sully also acts as the mentor type figure for Nate.
Gumshoe thinks he has one of these going on with Edgeworth. Sometimes it's truer than others. Edgeworth does seem very fond of him, and has saved him from getting fired on several different occasions. But he's still very frequently annoyed by the bumbling detective.
Adrian Andrews and her boss, Celeste Inpax had a very close friendship with each other before Inpax committed suicide, which sent Adrian into depression. After regaining her happiness from the aftermath of Matt Engarde's trial, Adrian becomes close friends with Franziska Von Karma, even going on holiday vacation with her and learning how to use the whip.
X & Zero in the Mega Man X games, who were originally created to kill each other. By Mega Man X5, the Ho Yay was waist-deep. It doesn't help that Zero looks like a girl.
The Battle Network series give us Lan and MegaMan.EXE and Geo and Omega, though it's somewhat padded by them having other friends as well.
Then again, in Lan's and MegaMan.EXE's case, they've been pulling each others' asses outta frying pans for as long as the series has run. MegaMan is Lan's dead older twin brother Hub, resurrected as a digitized Replacement Goldfish by their father. So their bond is pretty justified.
The fourth game also places a lot of emphasis on the "life partners" aspect of the trope, as they live together and are jointly raising a child.
Marcus Fenix and Dominic "Dom" Santiago from the Gears of War franchise, to the point where Dom will break into an abandoned prison filled with subterranean mutants in order to free Marcus. And sure, Dom's got a long-lost wife, but she conveniently dies during the second game.
Luis Lopez and Gay Tony from Grand Theft Auto DLC "The Ballad of Gay Tony". Now, admittedly, Gay Tony is, well, Gay. But that doesn't stop Luis and Tony from having a close, yet strictly platonic friendship. Luis the muscle and Tony the plan maker (Even if he's not a very good plan maker) They compliment each other's character development well. Both characters need each other. Tony helps Luis get back on his feet and teaches him business sense and Luis keeps Tony safe and his head on straight once he begins to descend into a drug bing. Friends that close are rare to find
Because they are the most famous Uber pairing in the game, the Medic and the Heavy from Team Fortress 2 can be described as hetero life partners. (The slashfic writers would disagree, but there you go.)
The Heavy: I love this doctor!
Furthermore, it's actually advised that this is the best combination for an Uber pairing due to the Heavy's large amount of health.
While every class has variations of "Thanks, doctor!" and "Follow me, doctor!", the Heavy seems the most enthusiastic. In addition, he has several lines boasting about the fact that "his" doctor is still alive. The Medic's lines are more generic ("Ve did it, camarade!"), but the fact that many Medic players follow Heavies almost exlusively would seem to confirm the hetero-life-partner relationship, if only in Fanon.
This video also further confirm this since clearly, the two get along and the way they prepare for Übercharge show that they have some sort teamwork dynamic.
The BLU Soldier and RED Demoman had one of these going on before the Administrator broke them up.
Sora and Riku from Kingdom Hearts. Sora reacts with such heartfelt gladness over Riku's return in the second game that it overshadowed his reunion with his nominal love interest Kairi. It was obvious enough that one webcomic artist did a parody of the scenenote It should be said that last time Sora saw Riku was probably a year and a half prior, and he had been trapped in the Realm of Darkness. Sora was worried about Riku's wellbeing, since Riku could've been dead for all he knew. Kairi, on the other hand, had been safe on the island that whole time, Sora knew where she was, knew she was safe. While she does get kidnapped, it was only for a few days, and her whereabouts were still known.
Roxas and Axel, depending on your interpretation.
Saix and Axel were shown to have had this dynamic from their time as a somebodies (Isa and Lea) up to them joining Organization XIII. It's too bad that their friendship suffered when Saix started becoming a vessel for Xehanort's heart...
Another possible example: Zexion and Lexaeus, as seen in Chain of Memories. They're intellectualequals and often conduct civil, sophisticated conversation in each others' presence. The latter even goes as far as to silence Vexen when he becomes too condescending towards Zexion over his rank. Lexaeus' Secret Report in Days even says that Zexion's the only one he can trust, and Lexaeus is shown asking for Zexion's forgiveness when an "Ansem"-possessed Riku kills him. When the two of them regain their humanity in 3D, they are seen in the same room where Lea wakes up. Everyone else seemed to have gone elsewhere, but those two are good pals enough to not be separated.
Genesis Rhapsodos and Angeal Hewley could also fit—Angeal ditches the organization he's worked for for who knows how long for Genesis, so they must be some damn good friends at least.
Cloud and Zack. Zack even looks after the comatose Cloud and even died defending him against hundreds of Shinra soldiers. If that is not the height of male love, I don't know what is.
Yuna and Rikku in Final Fantasy X could be said to be this, seeing as they formed the Gullwings together after the first game.
One could also make an argument for Jecht/Braska/Auron as well. So much so, in fact, that when Jecht becomes Sin, Auron essentially acts as a godfather for Tidus and is the one person shown to be able to speak to Sin, which sets the plot in motion.
Vanille and Fang from Final Fantasy XIII could qualify as this even though many fans consider them to be Ambiguously Gay. However the nature of their relationship is not really elaborated upon despite the Ho Yay.
Noctis, Ignis, Gladio, and Prompto are a four-way version of this in Final Fantasy XV, where they all travel together almost throughout the entire game.
Well, more this one involves than two perhaps, as Star Wolf is a trio of male mercenaries who have shared their lives together, being Wolf, Leon and Panther. Also, it is hinted that Wolf and Leon have been together longer, going way before the events of Star Fox 64...though well...Leon seems to be enjoying his partner for sadomasochism.
In Shadowverse, Arisa has this kind of relationship with Losaria. Her story arc revolves around trying to rescue her.
Sonic and Tails, to the point that games that also make Tails playable within normal 2D platformer often also have the option to have him follow Sonic throughout the levels whether controlled by the second player or by the AI, an option usually, but not always, enabled by default. Even within games where he isn't playable, Tails often acts as the deuteragonist even if almost none of the other main cast appear in the game simply because of how close he is to Sonic the Hedgehog.
Sword of Flame, for example, has Kent and Sain. The pairing of two Cavaliers, such as this one, is especially common, as we also have Forde and Kyle in Sacred Stones and Lance and Allen in Binding Blade. Binding Blade has a non-Cavalier example, too, with the Fighter pair, Ward and Lott (probably the better example from Binding Blade, actually).
It's obvious that Soren is very attached to Ike (and crosses the line into Ho Yay quite often) since Ike was his first and according to Soren, his only friend. Ike respects Soren deeply, can sense his feelings unlike anyone else can, and is more than willing to let Soren cry on his shoulder when he starts breaking down about his past. They end up leaving on a journey together in Radiant Dawn if they have an A-support. Both get rather upset when the other dies or is injured in battle, although Soren more so. Hell, if Soren dies, he makes clear with his last words that he places more importance on Ike's life than the fate of the world. Yes, very close.
Soren: "Ike? Ike! This can't...It can't...What am I...If you're not here, what am I to do?"
Just as Marth and Kris (aka the male Avatar) form such a pairing in the game before Awakening, Chrom and Robin (a male Avatar from Awakening) are one of the prime examples of this. They even refer to each other as 'two halves of a whole'.
Chrom is also this with Frederick, though this relationship is largely due to Chrom being Ylissian royalty and Frederick being head of the Ylissian knights. Frederick appears to lean towards Ho Yay more than Chrom suspects, going so far as to immortalize Chrom in an Uncle Sam "I want you"-style poster - Chrom is stark naked in said depiction, or at least in the English version. The Japanese version merely shows a close-up of his face.
A female/female example, with Cordelia and Sumia. Their friendship is so strong that, in a DLC chapter, Cordelia almost gets into a Cat Fight with Maribelle over which girl has the best female friend. Not to mention, their possibleshared feelings for Prince Chrom never ever are an issue between them - Chrom's not even mentioned in their supports, which are all about their own bonds.
There's also Lissa and Maribelle from the same game, to the point that the latter refuses to share the former with anyone else!
Additionally, Say'ri and Tiki's supports lean very heavily towards almost full on Ho Yay, especially given the wording of their support conversations— You can tell the dev team really shipped them.
Fire Emblem Fates has Azura and Corrin (aka the female Avatar) to the point that they almost mirror Chrom/Robin.
And while we're at it, we have Kagero/Orochi, Elise/Effie, and Sakura/Hana.
Hinata and Takumi. According to a conversation between their sons, they even bathe together.
Laslow and Odin (aka Inigo and Owain respectively) have come a long way from their vitriolic territory.
There's also Thassarian and Koltira, two death knights who were close friends even when they served under the Lich King. Thassarian has, on multiple occasions, gotten in trouble with his superiors for rescuing Koltira. Koltira preferred arrest for treason and torture to fighting Thassarian at the Battle of Andorhal.
Varian and Bolvar, who were "like brothers"; Bolvar is even something of a father figure to Varian's son and helped raise him.
Tarenar Sunstrike and Gidwin Goldbraids from the Cataclysm expansion. Also known as "The Paladin Pals". While they bicker... quite a lot, their friendship is so strong it survived the fact that Tarenar is a Horde aligned Blood Elf and Gidwin is a Dwarf and part of the Alliance and when Gidwin's impatience gets the better of him and he winds up risking becoming a Death Knight Tarenar drops everything to go rescue him.
Anren Shadowseeker and Tholo Whitehoof in the Firelands content. After one quest Tholo even says, "Anren and I might no longer face the terrifying risk of being separated from one another." D'aww!
Thrall and Rehgar Earthfury. Rehgar sees Thrall as a role model and older brother of sorts, helping him to resurrect the Horde's shamanic traditions. They were the subject of a popular ship, until Thrall got married. Unfortunately, from the point of view of many fans, Rehgar has been kind of written out of the story.
Anduin Wrynn and Wrathion, the new Aspect of the Black Dragonflight. Despite Anduin's history with the Black flight, he chooses to spend all of his time in Pandaria with Wrathion. Wrathion also shows up personally in Stormwind, risking attack from his many enemies, to warn the young High King about N'Zoth's plans: even though he knows Anduin likely blames him for Varian's death. Also the subject of a popular ship, though not a terribly serious one.
Although they're not as close as later Magician/Fool friendships, Junpei and Makoto have a similar bond to Mitsuru and Yukari. Junpei is jealous of Makoto's strength, but Junpei gradually comes to trust and care for him.
Yu Narukami and Yosuke Hanamura definitely have shades of this if you develop Yosuke's social link. In point of fact, a Fan Nickname for Yosuke is Brosuke. Yosuke always refers to Yu as "partner", and Persona 4: Arena shows that Yu reciprocates the label.
Yosuke: There's still nothing here, but I have family and friends...and you.
Let's not forget Chie Satonaka and Yukiko Amagi, who have been close friends since childhood, thanks to a dog.
The Brocana continues as The Magician Arcana Morgana and The Fool Arcana Akira Kurusu/Ren Amamiya(Main Character) are extremely close. Morgana acts as the MC's conscience and the two spend most of their time together. As this Confidant is mandatory, the partnership is shown regardless of player choices. Morgana makes it clear he wants to stick it out with the MC no matter what.
Although not a part of the Magician Arcana as past best friend characters have been, Chariot Arcana Ryuji Sakamoto can also be considered this to the protagonist. Not only is Ryuji the protagonists first available confidant and friend, he noticeably appears as an alternative option in most story events that would otherwise be spent with a datable female character, even to the point that if the player choses to forego a romance route entirely, Ryuji will automatically show up on Valentines Day instead and give the protagonist chocolate.
In Devil Survivor, Atsuro is, in spite of the game's alignment-based structure, the one party-member who will follow you no matter what.
Same would probably go for Daichi in the sequel. This kind of relationship between him and Hibiki is more apparent in the anime version, however.
Touka and Karura after the final boss fight in Utawarerumono. Unfortunately for any yuri fanboys out there, they're confirmed to still be hetero, as their mutual berserk button is disrespecting their relationship with Hakuoro.
Ryu and Ken from the Street Fighter franchise. Guile and Charlie may count too.
Alluded to in Wreck-It-Ralph after a day of beating each-other up. Ryu and Ken act totally buddy/buddy and go off to get drinks together.
Ratchet & Clank are also this. In fact, the "life" part is very literal, having been together for nearly the same amount of time that Clank has been conscious. Also within the series are Qwark/Skrunch, Rusty Pete/Captain Slag (although, being pirates, they may not be heterosexual life partners), and Cronk/Zephyr.
With Sparx. In the backstories for both the original series and the Legend of Spyro series, they were born on the same day and are inseparable, especially since Sparx functions as Spyro's health meter.
With Hunter. Ever since Ripto's Rage, the two have been seen going on several adventures together.
A female player character and Dawn Star in Jade Empire.
Possibilities abound in Neverwinter Nights; any henchman can serve as this if you are the same gender, though Nathyrra/female player and Valen/male player are the best examples.
Various fan-made expansions have examples; your character and your henchman (if same-sex) in the Shadowlords arc definitely qualify, as can the player and Llomir in A Hunt Through the Dark (depending upon your interpretation). A Hunt Through the Dark also has the Amazon Brigade Company of the Catlash, which probably counts.
In the fanfic, it's also rather common for Canderous and Carth to come to this - despite the fact they probably did face each other from across a battlefield or two.
In the origin stories in Dragon Age: Origins, the Mage, Dwarven Commoner, and Dalish Elf each have Heterosexual Life-Partners (well...however you take it, depending on the PC's gender) who also serve as their partners during the beginning of the game. However, they're pretty quickly forced to leave them behind when they're the only one recruited into the Grey Wardens. Depending on how the player plays their cards, they can always find another one later on in a party member, especially noticeable with a male Warden and Alistair or a female Warden and platonic!Leliana.
A female warden can also form this kind of bond with Morrigan (she at one point refers to you as not just a friend, but a sister), but it comes with a large side of Vitriolic Best Buds. This is especially obvious if you tend to be more good-aligned or are romancing Alistair.
The countries Canada and USA in eRepublik have a treaty that says they will "never give up on each other, never let each other down, and never run around or desert one another."
Dragon Age II has many possibilities, especially prominent with Hawke and Varric. The fact that Varric is the only squad member who isn't your sibling who you can't at least flirt with helps.
Also the fact that Varric is the only character who absolutely has to be in your party all the way through. You can kick Anders and Merrill out of the party, kill Anders for blowing up the chantry, send Fenris back to slavery, hand Isabela over to the qunari, and get rid of Aveline by siding with the mages. You can't avoid losing your sibling. But you can't get rid of Varric! He continues to be this to a male Hawke in Dragon Age: Inquisition, being the only person who he kept in constant contact with for the four years he was on the run. If Hawke sacrifices himself to save the Inquisitor and a Grey Warden ally, Varric is almost completely broken by the loss of his best friend.
Yui and Mako in Lux-Pain. It makes Mako's death really piss off Yui.
Live Powerful Pro Baseball's every success modes from the forth game including MLB Power Pros' have you work with a funny guy with large glasses (usually Yamada or Marvin) who is likely to be your best friend, roommate, and your personal Chew Toy.
It wouldn't be too much of a stretch for Yuri Lowell and Flynn Scifo from Tales of Vesperia to be this. Flynn sent out dozens of ships to look for Yuri after he fell from Zaude and Yuri would trust Flynn with his own life to the point where he actually offers his life for Flynn's when Flynn is arrested. This usually falls straight into, well, you know...
Rita and Estelle develop a very close friendship over the course of the game, and the stills in the credits seem to imply that they eventually become this, as they appear to be either visiting each other or living together in Halure. The only contention is theyhaveevenmoreromanticsubtext than Yuri and Flynn.
Jade and Peony in Tales of the Abyss. Jade is Peony's unofficial right-hand man. Peony's named a rappig after him, they're childhood friends, and Peony seems to be the only person on the planet who can out-snark Jade. He also occasionally calls him "my" Jade, but, uh, don't think too hard about that. Peony's in love with Jade's sister, we swear.
Luke and Guy from the same game would also probably fit the bill. Guy has been serving Luke since they were both very young, and he is the only one who goes back for Luke after Luke destroys Akzeriuth. You can even get a scene were Guy swears his Undying Loyalty to Luke.
Golden Sun: Dark Dawn shows this to be Isaac and Garet's relationship. They live in a cabin away from any settlements, their wives are nowhere in sight, they raised their sons together, and they spend the entire opening sequence acting Like an Old Married Couple.
Sonny and Veradux of the flash game series Sonny are definitely this, at least by game 2, where during the opening cutscene Vera shows genuine concern when Sonny has a flashback to the events that started the first game (part of which is a tutorial if you choose to play it when starting a new game in 2), and is quickly on his feet with his weapon at the ready when Felicity decides to use Sonny as a parking space for her motorcycle, but he gets a knife thrown into his face before he can fire a shot. In the first game, this trope gets lampshaded in dialogue the pair share at the beginning of the final zone of the main story:
Sonny: So how long do you plan on travelling with me?
ATLAS and P-body from Portal 2 can be considered an asexual example of this trope (although some fanartists depict them as being male and female).
In The Reconstruction, Dehl and Qualstio have shades of this. Justified, since when Dehl came from the mainland, he had just witnessed his entire family being killed, and had only an infirm Moke for companionship. Qualstio helped him and gave him shelter at the first opportunity, and so he's practically the only family substitute Dehl's had for a decade.
Mario and Luigi are brothers. This trope still applies, however, with the two's interactions: as either of them spring into action when Peach is kidnapped, they show large amounts of concern and anxiousness and act even faster when something happens to one of them. They are seen to still share a bunk bed in their adult years (or at least the same room depending on the game) and spend almost all their free time together and are always there for each other.
And from the same universe yet different game series, Donkey and Diddy Kong. When Donkey's banana horde is stolen, Diddy jumps at the call to help him. When K. Rool captured Donkey, Diddy got his own entire game just to help Donkey (granted, he had help from his girlfriend). It got so bad that K. Rool had to capture them BOTH by the 3rd game.
In The Legend of Dragoon Dart and Lavitz. While the amount of time they know each other is limited due to Lavitz being killed by Lloyd with a Dragon Buster Sword, the level of their friendship is obvious. There are several scenes throughout the game, including the closing scene, that highlights this.
English Language StarCraft II commentators Tasteless and Artosis often act like this. They have a Portmanteau Couple Name, Tastosis, and they refer to themselves as the "Casting Archon" Archons being a Unit from StarCraft that is made of two other units that literally mold together. Tasteless even calls Artosis his "Hetero-Nerd-Life-partner"
Adol and Dogi from the Ys series. They met in the first game and have been travelling companions pretty much ever since.
Valvatorez and Fenrich from Disgaea 4 could very well be considered this. Although, calling them heterosexual may be giving them too much credit...
Ezio Auditore and Leonardo Da Vinci in the Assassin's Creed II games pretty much function as this. Bro-hugs and sentimental moments abound. It's honestly probably the most touching relationship across all five games.
Marisa and Reimu from the Touhou Project. The spinoff manga in particular tend to show Marisa spending more time at Reimu's shrine than at her own house. Those who know the characters primarily through Fan Works might be surprised at how littleLes Yay there actually is between the two of them.
The hero and their partner in each game of the Pokémon Mystery Dungeon series always end up forming this sort of relationship. They're almost never seen apart once they meet and share a home in the latter two games of the three.
Magnus and Yumil from Ogre Battle 64. Childhood friends the former became a knight to protect the latter. The latter refused to use his Instant-Win Condition because it would kill the former.
Before their bitter rivalry started, Reaper and Soldier: 76 of Overwatch were best friends who stuck with each other through almost everything (the army, the first Omnic crisis, Overwatch). 76 even defended some of Reaper's more dubious actions, which resulted in the downfall of Overwatch.
From the same game, we have Reinhardt and Torbjorn, who have stuck with each other even longer than the above example, and are close enough that Reinhardt tells stories to Torbjorn's younger kids and mentors his daughter Brigitte.