KLM Royal Dutch Airlines will pull its service to Amsterdam out of Liverpool John Lennon Airport from 31 March 2012.
In a statement issued overnight, LJLA, part of Peel Airports, said: "In spite of good passenger numbers and improving route performance, the airline has made this decision following a review of their route network strategy in the current difficult economic climate.
"Peel Airports believes that in light of the strong passenger numbers and improving route performance there remains a strong case for a service from Liverpool feeding into a hub airport to offer onward global connections. The Airport Company will therefore be making every effort to replace this service.
"Passengers can of course continue to travel to Amsterdam Schiphol with easyJet on their three times daily service from Liverpool John Lennon Airport."
Craig Richmond, chief executive of Peel Airports, added: "We are naturally very disappointed that KLM have taken this decision, however we understand the challenging economic conditions that they and many others in the aviation industry currently operate in.
"This service has also been important for the Liverpool City Region, opening up global connectivity for travel to and from the region and it is for this reason that we will pursue all alternatives as we look for a replacement service to a hub airport.
Meanwhile, Peel Airports this week confirmed plans to sell a majority stake in its Durham Tees Valley International Airport outside Middlesbrough.
Both airports continue to suffer heavy losses for the group, which is now 65% owned by Vancouver Airport Services and 35% by Peel Group.