Life in Venice
In 1481, Paganino and Ugo were confronted by Ezio Auditore da Firenze, who was carrying a wounded Rosa. After the group exchanged words about their Guild, Paganino helped Ezio and Rosa get safely to their headquarters, where Antonio resided.
Siege of Monteriggioni
On 2 January 1500, the Borgia's armies attacked Monteriggioni, and Paganino remained, unnoticed, in Mario Auditore's study in the Villa Auditore. Around this time, Paganino came across Ezio in the study, to which Paganino asked the Assassin where the secret passage that he was taking led to. After receiving the information, Paganino left Ezio, claiming that he had to "go help the troops."
After the skirmish at the Colosseum Passion Play in August of 1503, Ezio saw Paganino behaving suspiciously in the area, and recognized him from the Villa attack. As Ezio called out to him, however, Paganino fled in panic.
Ezio pursued and tackled him, where he found that the thief was carrying Borgia documents. As the Assassin realized that Paganino was the traitor they had been searching for, and not Niccolò Machiavelli as La Volpe had suspected, Paganino defiantly declared "Long live the Borgia!" before impaling himself in the neck with Ezio's Hidden Blade.
- In the official artwork for the Siege of Monteriggioni, Paganino appeared alongside Cesare Borgia at Monteriggioni's gate. However, in both Brotherhood and its novelization, he was not present.
- Paganino's suicide in the game was similar to that of a courier from Assassin's Creed: Lineage. There, Giovanni Auditore da Firenze caught a messenger sent by Marco Barbarigo, and threatened him with his Hidden Blade. However, the messenger only said "My life is not yours to take, and my secrets come with me. See you in hell", before forcing Giovanni's blade into his throat.
- In the Brotherhood novel, Paganino instead committed suicide by thrusting his own dagger into his chest.