Assassin's Creed Brotherhood is mainly set in Rome, where Ezio Auditore leads the Assassin Brotherhood against the Borgia family.
The game continues Ezio's story after Assassin's Creed II. Rome is presented as a large open-world city under the influence of Cesare Borgia and his father, Pope Alexander VI. Ezio works to weaken Borgia control by liberating districts, recruiting Assassins, and restoring important landmarks.
Rome's setting reflects the game's historical period, the early 16th century. Players visit locations inspired by real sites, including the Colosseum, the Pantheon, Castel Sant'Angelo, and the Vatican area. The game compresses and rearranges history for its fictional plot, but its landmarks and political backdrop are recognizable.
A common mix-up is Florence, which is strongly associated with Ezio because it is a major setting in Assassin's Creed II. Brotherhood instead makes Rome the central city and expands the series' city-based exploration with a wider countryside region.