Dragon Age 2. Oh god, Dragon Age 2.... It was boring, it was dull, it was like they took the first game and just gutted it. Even the graphics, the one thing that consistently improves over time, were either the same or actually worse in DA2 than they were in Origins. How the hell does that even happen? It's just mind-boggling how much they screwed up on that title. It ended up being an okay average game, which for obscure and starting companies would be great. But Bioware is neither obscure nor just starting out, making it a major black mark on their record.
ME2 was also disappointing, but not nearly as much. I still liked the combat, so I didn't mind that, but I hated the mission structure and the ending? That was ridiculous and dumb. When I saw the new Reaper being created, that was when I stopped caring about the ME storyline.
Xenosaga Episode 1, and especially Episode 2. I started Xenosaga when only episode 1 was out. Being a huge fan of the PS1 game Xenogears, I played it eagerly... And was very disappointed. It just wasn't at all as good as its spiritual predecessor. A few years later I gave the game another shot though, and ended up loving it. Xenosaga Episode 1 is now one of my favorite RPGs, and definitely one of the most cinematic and beautiful to watch games. Unfortunately, then came out Episode 2, which managed to destroy all of that by completely changing the art style and many of the voice actors, making everything feel utterly foreign and strange. Imagine watching a beloved tv show, where the characters feel like your old friends, only suddenly they've all been replaced by slightly worse versions of themselves. Imagine having to watch a whole season of that. That's what Xenosaga Episode 2 felt like, and I still haven't managed to bring myself to complete it, despite hearing great things about the third game in the series.
Star Ocean: The Last Hope. Star Ocean: Till the End of Time gets a lot of crap for having the big "twist" in its storyline, but that never bothered me. The things that did bother me were the at times atrocious production values and terrible voice acting that the game featured. But despite these issues, it had a very fun combat system, fun world, fun characters, and fun storyline, and I loved it anyway. The Last Hope fixes some of these problems, at least in terms of production value. Unfortunately, the english version of the game features even more terrible voice acting than Till the End of Time, only this time the voices aren't for minor characters but some of the most major ones! Even worse, the storyline is frequently ridiculous and stupid, particularly toward the end when you learn what and who and why the bad guys are. Again, this isn't bad to the extent that DA2 is, but it was still highly disappointing, and these flaws kept a good game from being a great one.
Other notable candidates are Prince of Persia Warrior Within, FFX-2, FFXIII, and FFXIII-2.