The cause of the incident that downed the US Air Force CV-22 Osprey, which takes off like a helicopter but flies more like a plane, was under investigation, said the US-run International Security Assistance Force (ISAF).
"A US Air Force CV-22 Osprey crashed in southern Afghanistan late last night, killing three US service members, one civilian employee, and injuring numerous other service members," the alliance said in a statement.
The aircraft was carrying US forces and crashed about seven miles (11 kilometres) west of Qalat city in Zabul province, the military added. The nationality of the dead civilian was not immediately clear. A number of injured people were transferred for medical treatment at a military base.
Mohammad Jan Rasool Yar, spokesman for the governor of Zabul province, said a chopper came down due to technical problems near a village close to Qalat late Thursday, without specifying a precise time or the type of aircraft.
The Taliban claimed it shot down the helicopter, killing at least 25 but the insurgent militia routinely exaggerates its claims.
The insurgency, which has been concentrated in southern Afghanistan, has steadily intensified since the 2001 US-led invasion brought down the Taliban regime.
NATO and the United States are boosting their deployment to 150,000 in coming months as part of a counter-insurgency strategy designed to end the war quickly and allow American troops to draw down from July 2011.
The latest deaths in the aircraft crash would bring to 151 the number of foreign troops to have died during the war in Afghanistan so far this year.
In a previous NATO helicopter crash in Zabul on March 29, all 14 people on board were injured. Technical problems were also blamed.
That was the second such incident in a week, after a Turkish helicopter came down in the southern province of Wardak six days earlier, injuring four soldiers.
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