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Tear Jerker: Razors Edge
The conversation between Tali and Liara about how Tali wants Shepard to be happy with Liara when Tali's dying on the Broker's ship. The whole chain of events leading up to that conversation, really, but that brings it to a head.
Tali: "Tell him... sorry... that I love..."
Liara: "He knows."
Mordin's death. If you've already played the game, you knew this was coming, but what really sells it is the tape he leaves behind.
The way Shepard slowly falls apart, bit by bit, during Requiem. He knows that he's circling the drain, and things like making Garrus successor and replacement if he dies make it clear how much thought he's put into his death. In fact, at one point he notes that he's no longer afraid to die.
Shepard's Disney Death on Utukku is a definite Wham Episode, but the scene of a completely broken Tali crying on the floor of Shepard's cabin is just unbelievably cruel.
Legion's death is also much more emotional than Canon. Having more people be present for it is part of this though.