In Assassin's Creed Brotherhood, Ezio Auditore defends Rome from the Borgia family.
Rome is the principal setting of Brotherhood and the base from which Ezio rebuilds the Assassin Brotherhood. After the Borgia attack on Monteriggioni, Ezio travels to Rome and confronts Cesare Borgia, the game's central antagonist. He works with allies, recruits new Assassins, and weakens Borgia control across the city.
The game presents Rome as a large open-world environment containing famous landmarks, districts, and political strongholds. Its story draws on real Renaissance figures and places, while the conflict between the Assassins and Templars remains fictional. Florence and Venice are strongly associated with Assassin's Creed II, which is why they are common mix-ups. Constantinople becomes the main setting of Assassin's Creed Revelations, the later game that continues Ezio's story.