Ryanair will open a new base at Milan Malpensa on December 1.
The low-cost carrier will operate four routes — to London Stansted, Comiso, Bucharest and Seville — from the airport.
All will start on December 1, apart from Bucharest, which will commence the following day
Ryanair said it will make 28 weekly flights from Malpensa, where it will base one aircraft.
Its Stansted route will operate twice daily, Comiso once daily, Bucharest four-times weekly, and Seville three-times weekly.
David O'Brien, Ryanair's chief commercial officer, said: "We are pleased to add another key primary airport to what is already Europe's largest route network, as we continue to connect Italy with Europe's major centres of business.
"We will continue to operate and grow at Milan Bergamo Airport and as demonstrated by the success of our dual airport strategies in Brussels, Glasgow and Rome, Ryanair will remain the ideal choice for both business and leisure customers."
Earlier this month, Ryanair announced its schedule at London airports during summer 2016, including new routes to Sofia, Verona and Vilnius (see news, September 3).