Assassin's Creed Brotherhood is set mainly in Rome, where the Borgia family controls political and military power during Ezio's campaign. Ezio works to weaken their influence and rebuild the Assassin Brotherhood.
The central antagonist is Rodrigo Borgia, who appears as Pope Alexander VI, while his son Cesare commands military forces and seeks greater control. The game's Rome combines historical landmarks, papal authority, noble districts, and countryside surrounding the city.
Brotherhood differs structurally from Assassin's Creed II because most of its story takes place in one large open-world city rather than moving among several Italian locations. Ezio recruits and trains new Assassins, then sends them on missions across Europe while improving Rome's districts.
Rome is also the location of the Colosseum, the Pantheon, and the Vatican area as represented in the game. The city should not be confused with Venice, a major setting in Assassin's Creed II, or Constantinople, the main setting of Revelations.