More than 1,000 people have been killed in Afghanistan this year, the worst violence since the 2001 overthrow of the Taliban.
Violence has surged as NATO prepares to take over security duties from US-led forces in the south.
The latest clash occurred in eastern Nuristan province on Wednesday.
In a statement, the US military said that "coalition forces attacked enemy extremists in a remote area of the Kamdesh District while conducting security operations to interdict enemy movement through northern Nuristan."
"During the mission, four US soldiers were killed," the statement said.
The statement added that one soldier was wounded in the clash and was evacuated to a coalition hospital. He was in stable condition, it added.
Operation Mountain Thrust
The clash in Nuristan comes after the launch of a major US-led offensive called Operation Mountain Thrust against Taliban fighters in the volatile south ahead of the NATO takeover.
The Taliban are mostly active in the eastern and southern parts of Afghanistan, where they enjoy support among the local population.
More than 1,000 people have died in violence in Afghanistan this year, including more than 40 foreign troops, most of them Americans.
About 400 people were killed in May.