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The game starts with Captain America, Iron Man, Spider-Man, and Wolverine as the default playable characters. Some of the details of the story arcs have been either changed or rearranged in order to work as a cohesive story in the video game.

The story of Marvel Ultimate Alliance 2 takes its inspiration from a couple of actual story arcs that occurred in Marvel Comics, namely Secret War and Civil War. However, after a while, the Fusion subtitle was dropped and shortened simply to Marvel Ultimate Alliance 2. Unveiled via press release in February 2008, the follow-up to the Marvel Ultimate Alliance was originally titled Marvel Ultimate Alliance 2: Fusion.
