A "large number" of Americans were among those who died, according to a senior military official in Washington, who spoke on condition of anonymity because not all relatives had been notified. He said it remained unclear whether troops of other nationalities were among the fatalities.
The cause was not immediately clear. The Taliban claimed to have shot down the helicopter, but NATO said there were no reports of hostile fire.
It happened in Zabul province - rugged terrain where helicopters are heavily used to transport military troops spread over mountainous areas with few roads.
One other coalition service member, an Afghan National Army soldier and a U.S. civilian were injured.
So far this year, 525 U.S. and NATO forces have been killed in Afghanistan, surpassing the 504 killed last year. This year has been the deadliest for international forces since the war began in 2001.
The helicopter crash occurred in northwestern Zabul province in the early morning hours, according to a NATO official, who spoke on condition of anonymity because he was not authorized to disclose the location of the crash. Mohammad Jan Rasoolyar, a spokesman for the provincial governor in Zabul, said the helicopter went down in Daychopan district.
The NATO contingent in Zabul is dominated by U.S. and Romanian forces.
"I was sitting taking my tea," said Nakeemullah, 20, who works transporting livestock in the area. "I heard noise and I went outside to see what happened.
"I saw a lot of smoke in the sky," said Nakeemullah, who uses only one name. "It was far away for me, but I could see that it was a helicopter and it went down on the backside of the mountain where I couldn't see."
NATO said there were no reports of enemy fire in the area. However, Taliban spokesman Qari Yousef Ahmadi told The Associated Press by telephone that insurgents shot down the helicopter. The Taliban often exaggerate their claims and sometimes take credit for accidents.
Rasoolyar said NATO told local officials that the helicopter crashed due to mechanical problems.
"The Taliban were not involved in this crash at all," he said.
Also Tuesday, NATO said Afghan and NATO forces had conducted an operation Sunday and Monday to disrupt the Taliban's freedom of movement outside its heartland of Kandahar city, also in the south, killing at least 11 insurgents and destroying several improvised explosive devices.
Most helicopter crashes in the country have been accidents caused by maintenance problems or factors such as dust.
The worst helicopter crash for coalition forces was in August 2005 when two transport choppers clipped rotors and crashed in a western Afghan desert, killing 17 Spanish troops.
In May 2006, a Chinook crashed while attempting a nighttime landing on a small mountaintop in eastern Kunar province, killing 10 U.S. soldiers. That followed a 2005 crash in Kunar that killed 16 Americans. In February 2007, a Chinook helicopter crashed in Zabul, killing eight U.S. personnel.
Afghan troops have been killed in helicopter crashes as well. In January 2009, a top Afghan Army general for the western region of Afghanistan and 12 others were killed when their MI-17 helicopter went down in Shindand district of Herat province.
Also Tuesday, a suspected U.S. missile strike killed seven alleged militants in eastern Afghanistan's Paktika province, three Pakistani intelligence officials said. The province lies across the border from Pakistan's South Waziristan tribal region, a major militant stronghold that the Pakistani army has tried to clear.
NATO said it had no operational reporting on an incident of that description.
The CIA routinely uses missile strikes to take out insurgent groups, but most hit targets in Pakistan's tribal belt, a semi-autonomous and lawless stretch of territory that has a very porous border with Afghanistan. U.S. officials rarely discuss the covert missile program.
Two of the three Pakistani intelligence officials said the militants killed Tuesday belonged to an insurgent group led by Maulvi Nazir. Nazir is believed to have an agreement with Pakistani authorities that they will leave him alone so long as his men avoid attacks on Pakistani soil.
The officials said the militants had just crossed into Afghanistan when missiles hit their vehicle in the Khand Narai area in Paktika. Their bodies were taken back to South Waziristan. The Pakistan officials spoke on condition of anonymity because they are not authorized to speak to media on the record.
Meanwhile, five Afghan road construction workers were killed and four wounded when their vehicle hit a roadside bomb in Shinwari district of Parwan province Tuesday, said Shinwari police official Abdul Shakoor. Parwan is in northeastern Afghanistan.
The violence follows a spate of attacks around the country as it held parliamentary elections on Saturday. Officials said militant attacks on election day killed at least 21 civilians and nine police officers.
Results of the elections could take weeks or even months to compile.
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Associated Press writers Mirwais Khan in Kandahar, Ishtiaq Mahsud in Dera Ismail Khan, Pakistan, and Anne Gearan in Washington contributed to this report.
