Prerequite: Had to be somewhat hyped pre-release by the media, fanboys, etc
I would go with Mass Effect 3. Without going into too much spoilers (although this is few years old and most know what happened), the ending retrospectively ruins Mass Effect 1 and 2. All that hard work and meticuously decisions made thru the first 98% of the trilogy ruined by the ending. The redone ending is "too little, too late". You can't undo 1st impressions.
Other notable disappointments:
Killzone 3 (single player campaign is horrible but the multiplayer was good)
Grand Theft Auto 4 (vastly inferior to San Andreas in every way except for having better graphics)
Halo 4 (the ending is a short QTE fight with the boss with a somewhat boring story)
Dead Island (this is a close second to Mass Effect 3 but this was a new IP, the trailer had everyone talking)
Medal of Honor 2010 (the developers was talking beef to COD until the game was actually released)
Pretty much every Call of Duty game since Modern Warfare 1 (except for Modern Warfare 2) (no explanations needed)
Aliens: Colonial Marines (again no explanations needed)
Final Fantasy 13-1, 13-2, 13-3 (yes, I preemptively put the 3rd game here without playing it)
Assassin's Creed 3 (Connor was a boring character and the Desmond storyline was forgettable)
Star Wars: The Forces Unleashed (not sure how this game got a sequel)
I'm sure there are other games that I've missed (nor played such as Black Ops Vita).
