Mullah Nazir died with at least five fighters when two missiles struck his vehicle in the north-west tribal district of South Waziristan.
He was leader of one of four major militant factions in Pakistan and was accused of sending fighters to Afghanistan in support of the Taliban.
Mullah Nazir is one of the most high-profile insurgents killed by drones.
He had survived several attempts to kill him, including a suicide bomb attack blamed on rival militants in November.
Mullah Nazir and his fighters were reportedly hit by the missiles on Wednesday while preparing to change vehicles.
His pick-up truck had apparently developed a fault in Angoor Adda, near South Waziristan’s main town of Wana.
Reports say Mullah Nazir’s deputy, Ratta Khan, was also killed in the attack.
Officials also said four militants were killed in a separate attack in North Waziristan, but their identities are not known.
Local residents were quoted as saying that they had heard on mosque loudspeakers announcements that Mullah Nazir was dead. Funeral prayers were said for him.
Mullah Nazir’s group is one of several militant factions operating in Pakistan’s restive north-west – in recent years there have been divisions among these groups.
Analysts say Mullah Nazir formed an alliance with the government and opposed the Pakistani Taliban, with whom he was at odds because he favored attacking US forces in Afghanistan rather than Pakistani soldiers.
After November’s attack on him, his faction told a rival group led by Taliban leader Hakimullah Mehsud, to leave the Wana area.
Reports say he was also seen as an enemy of militants from the Islamic Movement of Uzbekistan (IMU), and praised by Pakistan for expelling Uzbek and other foreign fighters from Pakistan in 2007.
His death could be a contentious issue between Washington and Islamabad, they add, because the Pakistani military views commanders like him as key to keeping the peace internally.
For years, he was a key figure involved in supplying fighters and support to the Afghan insurgency.
Pentagon spokesman George Little said he could not confirm Mullah Nazir’s death but added that, if true, it would be “a significant blow” to extremist groups in the region.
It would, he said, be helpful not only to the US and to Afghanistan but also to Pakistan because “this is someone who has a great deal of blood on his hands”.
Drone strikes have increased in frequency since President Barack Obama took office in 2009. Hundreds of people have been killed, stoking public anger in Pakistan.
The dead include senior al-Qaeda and Taliban leaders, as well as an unknown number of other militants and civilians.
The US does not normally comment on individual drone operations, but last year it emerged in the New York Times that the US president had personally approved or vetoed each drone strike.
Islamabad has called for an end to the attacks saying they violate the country’s sovereignty, but analysts say Pakistan has privately sanctioned such actions in the past.
Militants killed by drones in Pakistan
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