Messina Denaro, who had a power base near the western Sicilian port city of Trapani, was considered Sicily's Cosa Nostra, the top boss even while a fugitive.
Denaro was captured at the Palermo clinic, where he received treatment for an undisclosed medical condition. He was the last of three longtime fugitive top-level Mafia bosses who had for decades eluded capture.
Messina Denaro was tried in absentia, convicted of dozens of murders, and faced multiple life sentences. He is set to be imprisoned for two bombings in Sicily in 1992 that killed top anti-Mafia prosecutors Giovanni Falcone and Paolo Borsellino, Falcone's wife, and several of their bodyguards.
Italian Premier Giorgia Meloni tweeted that Messina Denaro's capture is a "great victory of the state, which shows that it doesn't surrender in the face of the Mafia."