Megaman Battle Network 4 - MMBN3 was a great RPG. Incredibly in depth customization and combat system, great world, fun characters, solid story, good music. Really a great, underrated game. Then MMBN4 comes along and destroys everything. Inferior translation, graphics, customization, music, plot, world, interaction. Every single aspect of the game is inferior to its predecessor, which is why it is on my list as "worst sequel of all time".

Master of Orion 3 - Fortunately I missed this one when it came out, and got to watch my dad play it first. Holy hell, did these people ever mess up a game. They seem to have forgotten everything that made the series wonderful. A true convoluted mess. Possibly a worse sequel than MMBN4, but I haven't played it myself, so I am not going to stick that title on it.