Budget airline Flybe is dropping direct flights from George Best Belfast City Airport to London Gatwick.
The company confirmed it had sold all of its Gatwick arrival and departure slots to rival Easyjet for £20 million.
The decision to withdraw from its main hub airport will particularly affect Northern Ireland commuters and travellers connecting to other destinations.
Easyjet, which operates out of Belfast International Airport, is unlikely to retain the City link.
In a statement Flybe, which has had to cut around 10% of its workforce, accused Gatwick's owners of trying to squeeze out smaller air carriers with charges and claimed fees had amounted to a 102% rise over the last five years.
"No business can swallow such a massive increase in such a short period of time and it is with real regret and some anger that we have made this decision.
"Flybe fully appreciates the implications this will have not only on Northern Ireland passengers but also on the wider regional economy which has come to rely on the convenient lifeline connections we provide to Gatwick."
Jim French, Flybe's chairman and chief executive, added: "We have to accept the ugly reality that Gatwick simply doesn't want smaller, regional aircraft at their airport and, with the absence of a regional aviation strategy and the Government's penalistic and ludicrous policy of charging air passenger duty (APD) on both legs of a domestic flight, I'm afraid it's inevitable that high frequency services from the UK's regions will ultimately be squeezed out of Gatwick, as they have been from Heathrow."
Services will be maintained until the end of March next year. Other routes out of Belfast City Airport are unaffected by the changes.
A year ago, Flybe ended its flights from Belfast City Airport to Bristol citing unsustainable passenger numbers.