Diablo 3 is by far the worst sequel and the worst game I've ever played in my life. I was such a huge fan of Diablo, and especially of Diablo 2. Everything about Diablo 3 was a complete bastardization of the series I once loved, and I do mean EVERY SINGLE ASPECT. I could write a dissertation on how it's such an epic fail, but I'll leave it at that.
Honorable mentions:
James Bond
Every James bond game after Goldeneye. I bought the next one after Goldeneye and it was horrible. I think it was "Die another Day."
Perfect Dark (xbox 360)
Didn't do the original justice. Maybe it would have turned out different if Rare Ltd had been able to work on it. :-/
Oblivion
Yeah, I said it! Compared to Morrowind this game is lack luster. Now, don't get me wrong, it was an okay game, however it failed to draw me into the world like Morrowind. I couldn't stand all of the hand holding that had been introduced into the series. That said, it wasn't a killer of the franchise, just a really big let down. Skyrim was slightly better, but still had that hand holding element that Oblivion introduced. I feel that Bethesda just needs to incorporate a, "Hardcore," mode, meaning that things like waypoints and fast travel are eliminated or severely used sparsely.