In Assassin's Creed Brotherhood, Ezio Auditore works to free Rome from Borgia control.
The game is set primarily in Renaissance Rome, where the Borgia family and their allies control political, military, and economic institutions. Ezio returns to the city after the events of Assassin's Creed II and rebuilds the Assassin Brotherhood while opposing Cesare Borgia and his father, Rodrigo Borgia.
A major part of the game involves liberating districts from Borgia influence. Ezio destroys Borgia towers, recruits new Assassins, restores shops, and builds a network capable of challenging the ruling family. These activities make Rome feel like an evolving open-world city rather than only a backdrop for missions.
Rome was the center of the Papal States during the period portrayed. The game uses real locations and historical figures, but its conspiracy narrative is fictionalized. Florence and Venice are strongly associated with Ezio's earlier adventures in Assassin's Creed II, while Constantinople is the main setting of Assassin's Creed Revelations.