The 50 are accused of being members of four trafficking rings linked to Roberto Pannunzi, a mafia boss deported from Colombia to Italy on Saturday who is believed to be the world's biggest cocaine smuggler.
The groups were based in Rome - where the core of the operation took place - and were importing cocaine as well as other narcotics from South America, the police told reporters at a briefing in Rome.
"They used highly sophisticated methods of smuggling, melting narcotics into unsuspectable boxing equipment," said Lorenzo Sabatino, commander of the operation.
The trafficking rings worked in cooperation with the Italian mafia, particularly the Camorra based in Campania and the 'Ndrangheta centred in Calabria.
One of those arrested, Franco Lasi, is believed to be the head of one of the rings and is considered the most important catch.
When police broke into his house on Monday they found €100,000 in cash and a trapdoor through which Lasi hoped to escape in case of need.
In the weeks before his arrest Lasi had been organizing a shipment of 200 kilogrammes of cocaine from Columbia through links with Pannunzi.
The shipment had been due to arrive at the port of Naples, where members of the Camorra crime syndicate were in charge of guaranteeing a safe delivery.
In Italy the business of drug-trafficking is tightly tied to the mafia clans that control the territory of delivery and distribution and the main route is through shipments by air or sea from South America.