Uncharted 3. Uncharted 2 is one of my fave games of all time, and 3 just let me down in every way. The story bored me to death, the set pieces and locales just didn't wow me like they had before, and the shooting seemed worse.
Skyrim. Morrowind and Oblivion were both really fun, but I feel like skyrim felt stale after those two games. Not enough change, and a world that just didn't quite do it for me.
Little Big Planet 2. LBP 1 really captured my imagination. I spent about 300 hours in that game. I had 2 on launch day, but it just never did it for me the way the first game did.
Skyward Sword. Dear lord, my hype for this was immense. My favorite game of all time is Wind Waker, and this looked like that games second coming. I expected the sky to be like the ocean in wind waker, and I thought there would be lots of exploration. I got a very very padded out linear hand holding simulator.
Other M. (sigh)
Also, my biggest disappointment is the fact that burnout paradise never got a proper sequel. That was easily my favorite racing game of all time.