Glasgow Airport is to lose its 14-year-old route to Philadelphia to east coast rival Edinburgh.
However, Edinburgh's gain will also be at the expense of American's New York route from the capital, which is also being axed.
The airline operated an Edinburgh-Philadelphia service in 2014 but switched it to JFK in New York the following year.
American is now effectively reversing that decision - but this time Glasgow has lost out too, perhaps because the airline feels it cannot sustain a Philadelphia route from both cities.
The move also points to American losing the battle for Edinburgh-New York passengers against rivals United, Delta and Norwegian.
Glasgow's summer service to the US's sixth largest city will end next month and operate from Edinburgh between next April and October.
American said it was unprofitable "in the current high fuel-cost environment".
It follows Glasgow losing its only New York flights over the winter, which United ended last October.
A spokesman for Glasgow Airport said: “American Airline’s decision to stop its seasonal Glasgow-Philadelphia service is disappointing and a reminder of the challenges Scottish airports face in attracting and retaining routes.
“Our air connections should never be taken for granted and that is why we continue to urge both the Scottish and Westminster governments to work together to find a solution in order to introduce the proposed 50 per cent cut in air passenger duty as soon as possible.
“We continue to enjoy strong transatlantic links with a number of services across North America and remain Scotland’s leading long-haul airport."
Edinburgh Airport chief executive Gordon Dewar said: “We’re delighted to add Philadelphia to our options and offer yet another new destination in North America to our passengers.
“Both Edinburgh and Philadelphia are steeped in history and culture, and this link will open up our cities to new markets on both sides of the Atlantic.
"We know there is a continued and growing appetite transatlantic routes as our recent figures show these services are as popular as ever, so adding another destination is an exciting development.
“It’s also encouraging to see our already close relationship with American Airlines continue as they identify Edinburgh as an important city for their wider network, and we see them as a key partner in our plans.”
An American Airlines spokesman said: "Decisions to adjust our schedule, including the cancellation of our seasonal Glasgow-Philadelphia service for 2019, are based on a number of factors and are never made lightly, or in isolation.
"In the current high fuel-cost environment, American needs to be smart about where we use our assets.
"This includes addressing flights that become unprofitable in that environment.
"We are focused on serving Scotland by connecting Edinburgh with our large and well-placed hub in Philadelphia, offering extensive onward connections across the United States, Canada, Mexico and the Caribbean."