The man died following the crash on the notorious stretch of A1 dual carriageway at Banbridge in Co Down.
The road has been closed in both directionss
Emergency services are on the scene near The Outlet.
A second person has been taken to the Royal Victoria Hospital in Belfast with serious injuries.
The serious crash involved a rapid response paramedic and three ambulance crews being dispatched to deal with those injured.
Motorists have been asked to avoid the area while the PSNI’s Collision Investigation Unit examines the scene.