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In 1494, Piero de' Medici was exiled by Girolamo Savonarola, who had gained control over Florence using an Apple of Eden. As a result, Piero fled to Venice, where Savonarola's supporters were also attempting to spread their leader's influence.
Irritated at the prospect, Piero stood up to one of these heralds, causing a brawl between him and Savonarola's followers. However, before Piero could be killed by the herald, he was aided by Ezio Auditore da Firenze, a friend of his late father; the pair quickly parted ways again when Ezio embarked to Florence to take down Savonarola's rule.
- Piero was a student and possible murderer of his teacher Poliziano through the use of arsenic poisoning.
- A database image found inside the files of Assassin's Creed II suggests that Piero was originally set to appear in the game.