Delta Air Lines will fly between North Carolina's Asheville Regional and New York LaGuardia airports from 4 June.
Delta Connection partner Comair will operate 50-seat regional jets on the city pair, which represents the seventh destination for the western North Carolina facility.
While no carrier currently connects Asheville with LaGuardia, Continental Airlines offers daily flights to nearby New York Newark Liberty International airport via Continental Express partner ExpressJet Airlines, according to Innovata.
Delta's main rival in Atlanta Airtran is also preparing to launch new service from Asheville as three weekly flights to Orlando start 11 June.
While AirTran was offered an incentives package for the Asheville-Orlando service, Delta was not offered anything similar for the LaGuardia links, says an airport spokeswoman.