Beginning to crumble by the time of the sack of Rome in 1527, at the end of the High Renaissance the villa found itself at the center of Odet de Foix's battle for the conquest of Naples. With the villa's aqueduct ruined in the battle, a malaria epidemic broke out that destroyed his army, and the French were forced to withdraw. In the aftermath, nature took its course: the area around the Villa Poggio Reale returned to its natural swamp-like state, and years passed before the reclamation of the surrounding land began again.