While the NATO-led alliance didn't disclose the nationalities of the service members, a senior Afghan government official told CNN they were Americans.
The official, who did not want to be named, said the five were killed along with an Afghan soldier in Zabul province.
According to NATO, the troops were conducting a security operation when their unit came in contact with enemy forces.
That's when the casualties occurred, the NATO statement said -- but then it added this line: "Tragically, there is the possibility that fratricide may have been involved."
The alliance did not offer additional details.
Security operations have been stepped up ahead of the Afghanistan's presidential runoff election, which will take place Saturday.
While fratricide is the crime of murdering one's brother or sister, the military uses the term to refer to 'friendly fire' incidents -- troops killing or injuring their allies or comrades.
The New York Times quoted Zabul province's police chief as saying the unit came under attack by the Taliban and called for air support.
"The aircraft accidentally struck the position of the American soldiers, killing five of them along with at least one Afghan soldier," the Times report said.
A U.S. defense department spokesman said early Tuesday morning he didn't have a comment about the incident.
Since the Afghan war began in October 2001, 2,323 Americans have died there. Once the United States confirms these latest deaths, the number will rise to 2,328.
Also since the beginning of the war, there have been numerous fatalities resulting from friendly fire.
Among the more publicized ones were the 2004 death of Pat Tillman. Tillman, who became a national hero after he gave up a lucrative contract with the NFL's Arizona Cardinals to join the Army's elite Rangers force, was awarded the Silver Star, the military's third-highest combat decoration, after the Army said he was killed leading a counterattack.
Only later did the Army admit he had been shot accidentally by his own comrades.
Here are some of the others:
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