Originally a member of the gens Calpurnia, which claimed descent from Numa Pompilius, the second king of Rome, a Calpurnius Piso Frugi, he was adopted by Marcus Pupius, when the latter was an old man.
But he quickly deserted this party, and went over to Sulla, who compelled him to divorce his wife on account of her previous connection with Cinna.
After his praetorship he received the province of Spain with the title of proconsul, and on his return to Rome in 69 BC, enjoyed the honour of a triumph, although it was asserted by some that he had no claim to this distinction.
Piso served in the Third Mithridatic War as a legatus of Gnaeus Pompeius Magnus, who sent him to Rome in 62, to become a candidate for the consulship, as he was anxious to obtain the ratification of his acts in Asia, and therefore wished to have one of his friends at the head of the state.
In his consulship he gave great offense to Cicero, by not asking him first in the senate for his opinion, and still further increased the anger of the orator by taking Publius Clodius under his protection after his violation of the mysteries of the Bona Dea.