Matteo Messina Denaro spent 30 years on the run from authorities but was finally arrested in January, when he was suffering from cancer.
As his condition worsened in recent weeks he was transferred to a hospital from the maximum-security prison in central Italy where he was initially held.
Denaro once claimed to have killed enough people to fill a cemetery and was convicted of numerous crimes, including for his role in planning the 1992 murders of anti-mafia prosecutors Giovanni Falcone and Paolo Borsellino - crimes that shocked Italy and sparked a crackdown on the Sicilian mob.
He was also held responsible for bombings in Rome, Florence and Milan in 1993 that killed 10 people, as well as helping organise the kidnapping of 12-year-old Giuseppe Di Matteo, to try to dissuade the boy’s father from giving evidence against the mafia.
The boy was held for two years, then murdered.
Italian media say Denaro did not give any information to the police related to organised crime after he was seized outside a private health clinic in the Sicilian capital of Palermo in mid January.
He is reported to have undergone surgery for colon cancer in 2020 and 2022 under a false name.
A doctor at the Palermo clinic told La Repubblica newspaper that Messina Denaro’s health had worsened significantly in the months leading up to his capture.
The son of a mafioso, Denaro was born in the southwestern Sicilian town of Castelvetrano in 1962. He followed his father into the mob and at 15 was already carrying a gun. Police say he carried out his first killing when he was 18.
The Castelvetrano clan was allied to the Corleonesi, led by Salvatore “the Beast” Riina, who became the undisputed “boss of bosses” of the Sicilian mob, known as Cosa Nostra (Our Thing), thanks to his ruthless pursuit of power.
Nicknamed “‘U Siccu” (The Skinny One), Messina Denaro became his protege and showed he could be just as pitiless as his master, picking up 20 life prison terms in trials held in absentia for his role in an array of mob murders.
He went into hiding in 1993 as a growing number of turncoats started providing details of his role in the mob, but investigators believe he rarely wandered far from Sicily.
Police say he spent much of 2022 hiding in Campobello di Mazara, a town of about 11,000, a short drive from his mother’s house in western Sicily.
He communicated with other mafiosi via “pizzini”, small pieces of paper sometimes written in code distributed by messengers, some of which were intercepted by police.
He never married, but was known to have a number of lovers. Denaro wrote that he had a daughter, but had never met her.