The UH-60 helicopter crashed several miles east of Bagram air base in an area known as the East Training Range, said Jim Wilkinson, director of strategic communications at Central Command headquarters in Tampa, Fla.
"I can confirm that there are U.S. casualties and at this time this incident does not appear to be related to hostile action," Wilkinson said.
He said all four aboard were killed, but he declined to provide other details about them or the circumstances of the crash.
The helicopter and its crew were on a routine training mission, he said.
Wilkinson did not immediately have information on the military service or unit to which the four victims belonged.
Details were sketchy and officials said it was not immediately clear what caused the helicopter to crash. They stressed that it appeared to be an accident.
The UH-60, known as a Black Hawk, is a utility transport aircraft that is a key to the Army's mobility.
Bagram is the main base of U.S. military operations in Afghanistan.
The Black Hawk normally is flown by two pilots and a crew of two. It is designed to carry 11 combat-loaded, air assault troops, and it is capable of moving a 105-millimeter howitzer and 30 rounds of ammunition.
The Black Hawk was first deployed in 1978 and it made its combat debut in the October 1983 invasion of Grenada. It performs a variety of missions, including air assault, air cavalry and aeromedical evacuations. In addition, modified Black Hawks operate as command and control, electronic warfare, and special operations aircraft.
The last American killed in Afghanistan was Sgt. Steven Checo, 22, a member of the Army's 82nd Airborne. He was shot Dec. 21, 2002, while on a nighttime operation in the eastern province of Paktika, near the border of Pakistan.
Since U.S. military action in Afghanistan began in October 2001, at least five U.S. helicopters have crashed or had hard landings that have injured U.S. troops. Two Army Rangers and two Marines have been killed, and at least 11 other troops have been injured.
On Wednesday, U.S. special forces detained two men near the eastern Afghan town of Jalalabad suspected of making bombs. The men, whose identities were not released, were found with bomb-making materials.
In December, a hand grenade was hurled at U.S. special forces troops as they drove through Kabul, injuring the two men and their translator. Days later, a suicide bomber blew himself up in an assault on the international peacekeepers, killing two Afghan staff members and injuring two French aid workers.
There also have been increasing reports of renewed training of militants both in Afghanistan and Pakistan. These reports, including interviews by The Associated Press with men who have undergone the training, have coincided with the increase in attacks and uncovered plots.
Last November, an Iraqi identified as Akram Taufiq Muramy was arrested in Kabul. He reportedly confessed he wanted to kill President Hamid Karzai.
Earlier this month two men were arrested for allegedly plotting to assassinate Uzbek warlord Rashid Dostum.