American Airlines will end its services between New York's JFK airport and Brussels on 6 November.
The Oneworld carrier cites reviewed route performance, market forecasts and future outlook as reasons for the cancellation.
This move is in line with similar hub-to-spoke route cancellations by Delta Air Lines and United Airlines, which favour services to their alliance partners' hubs in Europe.
Delta will end its Memphis to Amsterdam service in September as it continues to shrink its hub in Memphis. United will also end services on its Houston Intercontinental to Paris route the same month, which was a legacy of Continental Airlines' previous membership in the Skyteam alliance.
American says that its passengers can still fly to Brussels on its Oneworld partners, British Airways and Iberia, via London's Heathrow airport and Madrid's Barajas airport.
The carrier operates a 187-seat Boeing 757-200 to Brussels.
Schedules in Innovata show that Brussels Airlines, Delta Air Lines and Jet Airways operate services between JFK and Brussels. Jet Airways and United operate the Newark-Brussels route.