I...I mean...guh......
Sorry, brain short-circuited a bit. Really, I can't choose just one, it's often a combination, but insane difficulty and repetition often kills it for me. There is nothing more frustrating than being stuck on that ONE mission (or one of many missions like that), or that ONE game. I'm looking respectively at Saint's Row 2 (Yahtzee may have breezed through it on normal, but fuck him, some missions take a perverse glee in killing you, especially by stunlocking you via car or insta-death explosives/burning car wreck) and Bioshock (Maybe I just suck at it, but I died more times than the nameless one in a smoothie-maker). Bad instructions also plagued Bioshock - "Invent the LAZARUS VECTOR!" "uh, okay, how do I do that?" "Invent the LAZARUS VECTOR!" "...fuck this, I'm gonna play mass effect."
Bad plots don't kill it all that much for me though, and only in the most extreme cases does bad voice acting hamper my enjoyment of the game. Graphics generally don't bother me a whole lot, but if a PS3 game looks like it's from the PS1, I notice. Bad gameplay is also a dealbreaker, I found Bioshock's controls to be stiff, unintuitive and all around stiff - speaking of Bioshock - BY GOD DID I EVER GET SICK OF THE MOTHERFUCKING HACKING!