A major search, involving ground forces and helicopters, was launched after the four men, from Syria, Kuwait, Saudi Arabia and Libya, were reported missing from the detention centre at Bagram airbase early yesterday.
Lieutenant-Colonel Jerry O'Hara, a US military spokesman, described the men as "dangerous enemy combatants" but did not identify them.
It is the first known escape from the heavily guarded detention centre, which is inside the sprawling Bagram base, and is a major embarrassment for the US military.
The men were reported missing at about 5am local time. Dozens of US troops could be seen stopping and searching vehicles every few hundred yards around the base and in nearby villages, while US helicopters flew overhead.
"We consider this a very serious business," Lt-Col O'Hara said. "These guys are dangerous not only to Afghanistan but to the world in general."
There had been no US casualties in the escape and he had no reports of violence or of any US personnel being missing.
"I can't give specifics on how they escaped," he said. "The circumstances surrounding the escape are under investigation as we speak."
He said the men, who would normally have been wearing orange prison uniforms, could still be on the massive base, about 30 miles north of the Afghan capital, Kabul, and it was being thoroughly searched by military police.
Kabir Ahmad, the chief of Bagram district, said the four escapees were Abdullah Hashimi, from Syria; Mahmoud Ahmad Mohammad, a Kuwaiti; Mahmoud Alfatahni, of Saudi Arabia, and Mohammad Hassan, a Libyan. He said he had heard the men might have escaped from the base by car. "We are working to find out how they escaped," he said. "If they are in this area, then there's a strong possibility we will arrest them."
Photographs were circulated to Afghan security forces showing bearded men with shaved heads wearing orange prison uniforms.
The Bagram detention centre has housed hundreds of militant suspects since US-led forces overthrew the Taleban in late 2001 for refusing to give up the al-Qaeda leader, Osama bin Laden, after the 11 September attacks on the US.
The complex has also housed senior al-Qaeda suspects arrested in neighbouring Pakistan and elsewhere.
A US military spokeswoman said last weekend that about 450 militant suspects were being held at Bagram.
Yesterday's escape follows a painful episode for the US military in the eastern province of Kunar, in which it suffered its worst losses in a single combat operation in Afghanistan.
Sixteen American special forces troops were killed when militants shot down their helicopter on 28 June during a mission to rescue a four-man Navy SEAL reconnaissance team trapped in a firefight. Three members of the team were killed and one escaped.
The losses have made 2005 the bloodiest year for US forces in the country and have come amid an increase in militant violence ahead of parliamentary elections due to take place on 18 September - the next big step in Afghanistan's difficult road to stability.