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- For the Grand Master of the Knights Hospitaller, see Giovanni Battista Orsini.
Early in his career, he became a cleric of the Apostolic Camera. He was next an Auditor of the Roman Rota. He was a canon of St. Peter's Basilica. Finally, he became a protonotary apostolic.
When Charles VIII of France came to Rome on December 31, 1494 as part of the Italian Wars, Cardinal Orsini went with the pope to the Castel Sant'Angelo. On January 21, 1495, he was elected Camerlengo of the Sacred College of Cardinals. On May 27, 1495, with a French army approaching Rome, Cardinal Orsini left with the pope for Orvieto. He became archpriest of the Basilica di Santa Maria Maggiore in September 1498. On September 23, 1499, he left Rome for Milan as papal legate to the King of France; he returned on November 16. In 1500, he was again papal legate to the March of Ancona, leaving on his legation on July 29, 1500.
On July 12, 1502, he asked the pope for permission to visit the King of France in Milan; the pope did not agree, but he nevertheless left the next day, attending a meeting of the Orsini family at Lake Trasimeno to conspire against the pope's son, Cesare Borgia. Cardinal Orsini was soon thereafter arrested on the pope's orders and flung into the Castel Sant'Angelo. He died there twelve days later, on February 22, 1503, probably poisoned on the orders of the pope or Cesare Borgia.
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