[1] Born in Florence, he was the son of Lorenzo the Elder and Ginevra Cavalcanti, thus a nephew of Cosimo de' Medici and cousin to Piero the Gouty, de facto lords of the city from 1459.

He served the Republic of Florence as ambassador (to the pope in 1458 and to the Duchy of Mantua in 1463) and as Priore delle Arti ("Prior of the Guilds") in the Florentine municipal government (1459).

After Cosimo's death (1464), Pierfrancesco was initially a supporter of Piero the Gouty, but later sided against him; he was among the conspirators who participated in Luca Pitti's failed coup in 1466.

From his marriage with Laudomia di Agnolo Acciaioli he had two sons: Lorenzo (1463–1503) and Giovanni (1467–1498), who were later fierce opponents of Cosimo's line of the Medici.

His sons were adopted by their second cousin Lorenzo il Magnifico.