Which Assassin's Creed game is set mainly during the Italian Renaissance?

Assassin's Creed II is the Assassin's Creed game set mainly during the Italian Renaissance.

Released in 2009, the game follows Ezio Auditore as he becomes an Assassin and pursues those responsible for destroying his family. Its historical setting spans roughly the late fifteenth and early sixteenth centuries, a period associated with major artistic, political, and intellectual change in Italy.

The game recreates several Renaissance locations, including Florence, Venice, Monteriggioni, and Forlì. Historical personalities such as Leonardo da Vinci, Niccolò Machiavelli, and Lorenzo de' Medici are woven into its fictional narrative.

The broader series also uses Renaissance Italy in related titles. Assassin's Creed Brotherhood continues Ezio's story mainly in Rome, while Assassin's Creed Revelations moves him to Constantinople. Therefore, those games share the era and protagonist but are not the title most specifically identified with the Italian Renaissance setting.