Surprisingly, I really like a lot of Sci-Fi games even though I wouldn't say that's my favorite genre, and I don't want to choose from all of them, so I'll give credit to each for being "the best" in their own way:
Penumbra: Black Plague - Most intense story. It makes you want to know what happens next and it's always good for another surprise. Also thought-provoking.
Deus Ex: Human Revolution - Most innovative. The best dialogue system in a video game yet, truly making dialogue a challenge while also giving the system some clever spins.
Bioshock 2 - Best combination of gameplay and story. Gameplay mechanices and story elements blend into each other perfectly.
Fallout New Vegas - Most enjoyable game, most interesting setting.
Portal 2 - Most creative.
Mass Effect 2 - Best characters. Not necessarily the best-written characters, but because there are so many of them, with each getting their time in the spotlight. You learn about their strengths and flaws, and you get to help them resolve their conflicts.