The deaths were a fresh reminder that the conflict is nowhere near over for some US troops, who will keep fighting for at least two more years.
Pentagon spokesman Rear Adm. John Kirby said the five American troops were killed yesterday "during a security operation in southern Afghanistan."
"Investigators are looking into the likelihood that friendly fire was the cause. Our thoughts and prayers are with the families of these fallen," Kirby said in a statement.
The deaths occurred during a joint operation of Afghan and NATO forces in the Arghandab district of southern Zabul province ahead of Saturday's presidential runoff election, said provincial police chief Gen Ghulam Sakhi Rooghlawanay.
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After the operation was over, the troops came under attack from the Taliban and called in air support, he said.
"Unfortunately five NATO soldiers and one Afghan army officer were killed mistakenly by NATO airstrike," Rooghlawanay said.
However, special operations forces often come under fire on joint operations and are responsible for calling in air support when needed. Because of constraints placed by President Hamid Karzai, such airstrikes are usually called "in extremis," when troops fear they are about to be killed.
Airstrikes have long caused tensions between the Afghan government and coalition forces, especially when they cause civilian casualties.
Airstrikes that kill coalition soldiers are far less common. One of the worst such incidents came in April 2002 when four Canadian soldiers were killed by an American F-16 jet fighter that dropped a bomb on a group of troops during night firing exercise in southern Kandahar.