Okay, yes, The House of the Dead is infamous for its cheesy voice acting, especially in the earlier games. But that doesn't mean it's impossible to get a little something in your eye as you play.

As this is a Tear Jerker page, all spoilers are left unmarked.

The House of the Dead

Thomas having to watch his fiancee slowly die in the aftermath of the Chariot boss fight. It can be averted if you get the good ending, though.

On the contrary to what's described on the Heartwarming page, failing to save a civilian accompanied by another civilian is saddening, as a short interaction scene will show one of the civilian's friend or significant other approaching the dead body and mourning for it.
In one route in Muddy (chapter 2), you hear a woman scream as she's thrown against a window from an unseen creature and dies, prompting you to enter the house. If you blast off all the creatures inside, you save an adolescent woman and a little boy. It turns out they were the woman's children. Both of them then approach their dead mother and weep beside her dead body. This is especially saddening because this is the aftermath even though you just saved two people.
- This just proves one of many instances of Fridge Sadness; Four agents (five if Rogan's appearance is canon) can only do so much that not everyone could be saved, especially when the two controlled by the players take a separate path throughout the stages.
  - Considering you only go through this particular path if you fail to save a child civilian being chased by a Bob, it begs a Sadistic Choice in terms of Fridge Horror: Is it better to let that family die so they're Together in Death, or have the woman's children live with the pain of losing their mother in a creature invasion? Either way, this branching path dooms at least one child to die.
Failing to save a child civilian often breaks the heart of players.

The game reveals the reason why Curien went as far as researching the nature of life and death: he was desperate to cure Daniel, his terminally ill son. In fact, when he realized that the research was bringing harm, he considered shutting it down, but Love Makes You Evil and he proceeded anyway. While this doesn't excuse the things he had done, it does cast him as more than a Mad Scientist-wannabe.
Yukio, the Rogan Commando that gets killed in the beginning of Chapter 0 and is the first-on screen cutscene death. In chapter 5, Lisa and Daniel head towards the Wheel of Fate and Yukio's dead corpse rises as an undead, knowing how the late Rogan Commando's mission was to stop the Wheel of Fate, Daniel didn't want to fight him but has no choice.
Yukio: We're humanity's last hope! We cannot lose!
Yukio: *When he gets up each time* That was for my buddies!
Curien as the Wheel of Fate is so far removed from humanity that Daniel can no longer recognize him as his father and becomes the one to inflict the killing shot.

All of Kate's Genki Girl and optimism to reach the outside world again is obviously set up as a Dramatic Irony so she can suffer greatly when she finds the truth, because the game is an interquel and we already know the truth...and when it finally comes clean in Chapter 4, she breaks down. Hard.
James: My god...
Kate: No, this can't...
- The next chapter, Kate doesn't talk for the first half of the chapter. When she does, she is not as talkative and it seems as though she doesn't have a care for the world. From this point onward, say goodbye to Kate's Narm Charm Bond One-Liner.
- What makes it sadder is that Kate is, if her lines are of any indication, heavily implied to be a local of Venice (or something resembling it). James is not, so seeing the city's destruction doesn't pack up as much punch to him.
- The chapter's name? Despair.^note
James getting struck by one of The Star's final attacks at the end of Chapter 5 and having to be physically escorted by Kate on the rest of their way to the top of the tower.
James' Heroic Sacrifice. Kate's scream, contrary to expectations, is not narmy.
Kate: JAMES!!!!