About 150 members of the Italian special forces of Sicily are looking for Matteo Messina Denaro.
Dozens of houses belonging to close associates of the mobster have been searched on the island since Friday morning.
Messina Denaro is considered the supreme godfather of Cosa Nostra of Sicily, one of the largest mafia organizations in Italy.
He was sentenced in absentia to life in prison for the murders of Judges Giovanni Falcone and Paola Borsellono, who were killed in two bombings by several bodyguards in 1992, and for other murders.
Messina Denaro has been on the run since 1993.
“Mafia bosses can flee their hometowns, but they will return once and for all,” anti-mafia prosecutor Federico Cafiero told Rai 1.