US spokeswoman Lieutenant Colonel Michele DeWerth said two American soldiers were wounded when their convoy was attacked late on Saturday near Gardez, 100km south of the capital, Kabul, in Paktia province.
"Four unidentified anti-coalition militia troops were killed, two were injured and were taken for medical care, and two were detained," DeWerth said.
"Air support was used," DeWerth said, but provided no further details.
Yet, provincial police chief General Haygul Salemankhel said the shooting occurred because of a mix-up as the convoy approached a police checkpoint at night.
He said three of his men were killed and two injured.
"Because of a misunderstanding, they opened fire on each other," Salemankhel said.
"The Americans are patrolling around the city all the time, and I don't know what triggered this," Salemankhel said. "We're still investigating."
Paktia is in a broad swathe of territory along the border with Pakistan where about 15,000 US-led troops are battling fighters, apparently led by the Taliban.
More than 200 people have been killed in conflict across the country so far this year, most of them in the troubled south and east, casting doubt on plans to hold the country's first post-Taliban elections in September.