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Piso was extremely well liked throughout Rome. Through his father he inherited connections with many distinguished families, and from his mother great wealth. Piso came from the ancient and noble house of Calpurnii and he distributed his great wealth among many beneficiaries of all Roman social classes. Among a wide range of interests, Piso sang on the tragic stage, wrote poetry, played an expert game of draughts, and owned a villa at Baiae. He was the son of the consul, Lucius Calpurnius Piso and his wife Licinia, daughter of consul Marcus Licinius Crassus Dives and sister of Roman Senator, Marcus Licinius Crassus Frugi.
Piso was tall, good-looking, affable, and an excellent orator and advocate in the courts. Despite these facts Piso's overall integrity was questionable. According to Tacitus, Piso used his eloquence to defend his fellow citizens and was generous and gracious in speech, but lacked earnestness and was overly ostentatious, while craving the sensual. In 40 AD, the emperor Caligula banished Piso from Rome after he took a fancy to Piso’s wife. Caligula forced Piso's wife to leave him, and then accused Piso of adultery with her in order to establish cause for banishment. Piso would return to Rome one year later after Caligula’s assassination.
In 41 AD, the emperor Claudius recalled Piso to Rome and made him his co-consul. Piso then became a powerful senator during the reign of Emperor Nero and in 65 AD led a secret initiative to replace Emperor Nero that became known as the Pisonian Conspiracy.
Piso leveraged senatorial anger with the emperor Nero to gain power. Already in 62 AD, there had been talk among those of senatorial rank, in the nobility, and among the equites that Nero was ruining Rome. By 65 AD, the city had endured the Great Fire of Rome and the persecution of the Christians, spurring groups of conspirators to come together under the leadership of Piso with the goal of killing the emperor Nero.
On April 19, 65 AD, the freedman Milichus betrayed Piso’s plot to kill the emperor and the conspirators were all arrested. In all, 19 were put to death and 13 exiled, revealing the massive scope of the conspiracy. Piso was ordered to commit suicide and so killed himself.
Piso was survived by his son, Calpurnius Piso Galerianus who married Calpurnia, daughter of Licinia Magna and Lucius Calpurnius Piso, who served as one of the consuls in 57. His son was executed in 70 for opposing Roman emperor Vespasian.