Vampire Rain: looked AMAZING from the trailers, seemed to be a good indie game combining Splinter Cell with vampires. In reality was just awful. PERHAPS the worst game I've ever played.
GTA IV: spent hours and hours on it, and came away no richer. It's just beautiful enough to keep you playing, but not rewarding enough to make you happy at the end.
Spore: amazing concept, there is an amazing game in there somewhere, but they just fell short somehow.
The Witcher: agree with many above. GREAT storyline completely ruined by horrible combat.
Dragon Age: see above. Wonderful story screwed over by stupid-ass combat.
There was a Star Trek Next Generation game for SNES that was GREAT in everything but space combat. You could do great on the away missions, the storyline, etc but the space combat kicked your ass every time, and it got to a certain point where no matter what you did you got destroyed. Ruined what could have been a great game.
Uplink. Great game ruined by a "eventually they have to fail" mechanic.
Floor 13. See above: "they eventually have to lose." Blarg.
Minecraft. Sorry everybody, I just can't get into it.
Brink. The hype was SO enormous, the trailers so enticing, but...they just effed it up somehow. No real plotline, no tutorial mission, and even the singplayer campaign plays like it's a multiplayer game with bots. And honestly, no discerning, tasteful person likes multiplayer, so who would like a shallow shadow of it?