Virgin Atlantic will start running its first domestic service next year, flying passengers between London and Manchester.
Chief executive Steve Ridgway said the move was in response to the takeover of BMI by British Airways' parent company IAG, rather than Virgin Trains' loss of the rail service between the two cities.
Flights between Heathrow and the North West will begin next spring using leased aircraft.
The airline will operate three daily flights to Manchester using Airbus A319 aircraft from March 31, but tickets went on sale on Tuesday.
Around 650,000 passengers travel between London and Manchester each year.
Manchester Airports Group chief commercial officer Ken O'Toole said: "We are pleased to see Virgin Atlantic increasing their presence in Manchester and to see competition returning on the London route, as that will be to the benefit of passengers flying from our airport."