In Assassin's Creed Brotherhood, Rome is controlled by the Borgia family at the start of Ezio's campaign.
The game begins after the events of Assassin's Creed II, with Ezio established as a senior Assassin. The Borgia, led by Rodrigo Borgia and his son Cesare, dominate Rome through political power, military force, and Templar influence. Ezio's objective is to weaken that control by rebuilding the local Brotherhood, liberating districts, and recruiting allies.
Rome is unusually central because Brotherhood places nearly the entire main campaign in one large city rather than dividing the story among several major urban maps. The city includes famous landmarks such as the Colosseum, the Pantheon, and Castel Sant'Angelo, presented through the game's Renaissance setting.
Florence and Venice were important in Assassin's Creed II, while Constantinople is the principal setting of Revelations. Those locations are therefore plausible but incorrect alternatives. Brotherhood also introduced a major form of Assassin recruitment and an expanded city-management structure.