"What If the Hulk Had Always Had Bruce Banner's Brain?" (Vol. 1 #2) has one of the saddest endings in the entire series. Not only do Bruce Banner, Reed Richards and Charles Xavier save the world from Galactus at the cost of their powers, Ben Grimm is turned back into the Thing - a more aggressive, mindless version of the Thing with the Hulk's super-jumping abilities. Unable to help him, the others are forced to let the authorities handle it, leading to Ben becoming this universe's version of the canon Hulk - a monster constantly on the run from the army. The really heartbreaking part? He's married and has a baby on the way in this story.
In "What If Someone Else Had Become — the Amazing Spider-Man" (Vol. 1 #7), all three stories end pretty tragically.
Flash accidentally kills Crusher Hogan when testing his powers and decides to become a hero to make up for it. But not being a science whiz like Peter, Flash never invents web-shooters, and so he falls to his death while fighting the Vulture.
Betty, due to using up all her web fluid posing for some pictures earlier, finds herself unable to stop the thief who ended up killing Uncle Ben. She's devastated when she finds out, leading her to blame herself and hang up her webs for good.
"What If Dr. Doom Had Become a Hero?" (Vol. 1 #22) has Doom reluctantly selling his wife Valeria to Mephisto in exchange for the rest of his kingdom... and immediately regretting it. After this, every year he tries to retrieve her — failing each time. The comic ends on yet another of his failed attempts to get her back.
"What If Uncle Ben Had Lived" (Vol. 1 #46) has Aunt May be the one who first hears the burglar break into the house, and thus, becomes his victim. Her last words?
...Ben...
And of course, Ben finds her only minutes afterwards.
Ben: May! May! ...I love you, May...
What makes this even sadder is that Ben and Peter aren't nearly as close as May and Peter were in the canon stories, because while the two do love each other, Ben simply doesn't know how to assume parental roles by himself, that's just not how men of his generation were brought up. He's a bit more involved in Peter's personal life than May was, but he just doesn't relate to him the same way.
"What If Destiny Had Not Destroyed Atlantis?" (Vol. 1 #41) initially starts out well as Namor is able to stop Paul Destine from destroying Atlantis, scattering its people, and killing his mother, and buries his Helmet of Power to prevent a repeat. But his long time being gone leads his tyrant cousin Byrrah to take the throne, and a hurt Namor refuses to help his people when Attuma attacks and conquers Atlantis, even when Neptune himself attempts to give aid. Eventually he returns to the kingdom and defeats Attuma, but his mother is dead, and the people are so broken from being under Byrrah and Attuma's rule that they go into exile, leaving Namor a king with no people—so in a roundabout way, Atlantis' destruction still occurred.
"What If the Invisible Girl Had Died" (Vol. 1 #42) is a heartbreaking portrayal of grief as the remaining Fantastic Four members and superhero community at large react to her death, especially Johnny and Ben's reminisces of Sue contrasting with Reed's descent into total anguish as he plots to kill Annihilus for it. The end of the story isn't much happier, as Reed pulls a Murder-Suicide on Annihilus, leaving Johnny and Ben behind.
Ben: I guess I wuz always hopin', Susie, that you'd turn around and kiss me, like the princess you wuz, and turn me from a frog, a big ugly bruiser with a size-five brain—into a prince... Course, I know what you'd say to all this. "Benjamin J. Grimm! Stop talking like that! You are a prince—to me!" ... Yeah, I can even hear you saying it. Well, Susie, guess I'll have to start actin' like a prince from now on—only it's gonna be awful hard without you around. Johnny: I remember what sis told me, when Mom died and I wouldn't come out of my room. I wanted to stay in there and starve to death. She said, "I know you want to have a hurt so bad that only Mom can come along and make it better. But she can't and how do you think she'd feel about it if she knew? Terrible. So you'd just better make yourself feel better." And I did. And I guess I'll have to do it again. Reed: My life is over.
"What If...Starring Fantastic Four: Tragedy In A Tiny Town" (Vol. 2 #109) revisits the Liddleville scenario from Fantastic Four #236, where instead of helping his teammates escape, Ben Grimm opts to stay in the miniature town, as here he feels he can finally be with Alicia as himself. By the time he realizes he made a mistake, it's too late, and the other members long since died trying to escape, with Ben finding their decaying bodies. The story ends with Ben and his family trapped in a microsized version of Doom's castle — only now Ben is in a synthi-clone of his monstrous Thing body, Alicia hates him for lying to her and putting his own happiness and insecurity over the lives of their family, and they don't even have the facade of Liddleville to comfort them in their imprisonment.
"What If...Starring Juggernaut: The Kingdom of Cain" (Vol. 2 #94) shows just how devastating the Juggernaut's immortality is. After killing the X-Men and Professor X in their first encounter, Cain Marko is left alone on a seemingly uninhabited Earth long after the Sentinels lay waste to it and killed everything living with a poisonous atmosphere. After destroying some of the last Sentinels for fun, realizing too late that they might have found a way to kill him, Cain finds a last group of survivors holed up underground...and is so eager to find someone to talk to that he breaks through all their defenses and exposes them to the poisonous air, dooming them to die like everyone else. But the Juggernaut, who is truly unstoppable, is left alive and alone forever.
"What If Flash Thompson Became Spider-Man" (2018) has tons of tear-jerking moments toward the end. Despite his apparent success as a hero, Flash is violent and oblivious to how he acts as a bully. When Peter tracks him down wanting to use Spider-Man photos to buy the isotope to cure Aunt May's radiation sickness, he finds Flash living in squalor and barely able to get by. Enraged and thinking he came to laugh at him, Flash punches Peter into the wall, killing him, and finally realizes what he's become. He tracks down the Master Planner and is buried under the rubble, lifting it up as he realizes he isn't a hero but could try to redeem himself to become one. The story ends with Flash saving Aunt May, who is told by a heartbroken Uncle Ben that Peter has died and cries in a wordless panel, and then turning himself in to the police.
"What If Spider-Man had Never Become a Crimefighter" (Vol. 1 #19) shows Peter Parker becoming a shallow, selfish celebrity who alienates himself from his aunt and uncle and gradually destroys JJ Jameson's life with both intentional and unintentional actions. It takes Daredevil being badly, perhaps mortally, injured during a fight with a Sinister Six led by Jameson (now mad with despair) to make Peter tearfully realize that he's squandered the great power given him for greed.
