Local officials in Pakistan said Mullah Nazir, the main militant commander in South Waziristan, was taken out when an unmanned US aircraft fired two missiles at his vehicle.
But a Pentagon spokesperson could not confirm the account.
"If the reports are true, then this would be a significant blow, and would be very helpful not just to the United States but also to our Pakistani partners," spokesperson George Little told reporters.
Nazir reportedly sent insurgents to Afghanistan to wage war on Nato-led troops and operated out of the tribal zone where militants linked to the Taliban and al Qaeda have bases on the Afghan border.
Pakistani officials said the drone strike on Wednesday killed Nazir and five of his loyalists, including two senior deputies.
Nazir, one of the highest-profile drone victims in recent years, had a complicated relationship with the Pakistani government, having agreed to a peace deal with Islamabad in 2007. Pakistani officials had hoped he could counter Pakistani Taliban insurgents.
He was understood to be close to the al Qaeda-linked Haqqani network, a faction of the Afghan Taliban blamed for some of the most high-profile attacks in Kabul and elsewhere in Afghanistan in recent years.
"This is someone who has a great deal of blood on his hands," Little said. "This would be a major development."
Washington has long urged Islamabad to crack down on the Haqqani network without success.
Drone bombing raids in Pakistan are run by the CIA and not by the Pentagon. Although an open secret, the CIA does not publicly discuss the drone air war, which officials believe has severely weakened al Qaeda's leadership in Pakistan.
According to figures compiled by a Washington think tank, US drone strikes against Islamist militants decreased in Pakistan's tribal regions for the second year in a row but intensified in Yemen.
In Pakistan, 46 strikes were carried out in 2012, compared to 72 in 2011 and 122 in 2010, the New America Foundation said, based on its compilation of reports in international media.
But Yemen saw an equally dramatic spike in the covert bombing runs, with strikes against al Qaeda in the Arabian Peninsula (AQAP) militants rising from 18 in 2011 to 53 in 2012.
COMMENTS (8)
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Taliban=Hate They have nothing to give but hate and spread hate at global level. Dear US, please kill the system which is producing Taliban. Thanks to US for killing them by Drones.
@saleem The Taliban don't fear death. They celebrate death . For them deaths = martyrdom
Dear USA please extend the scope of the drones to cover the whole of land of pure. These murderous thugs should have no place to hide and should live in constant fear of death.
US protecting their TTP investments. Nothing to see here, please move along.
Surely, next on their target must be one of their most wanted - Hafeez Saeed. It is a question of time now. Remember, you can run but you can't hide.
2013 starts with a bang!