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The strike late Tuesday, which officials said involved 18 missiles fired from eight unmanned spy planes, is the latest in a series of US attacks on the lawless tribal area near the Afghanistan border.
It is a known stronghold of homegrown Islamist militant groups and extremists who fled Afghanistan after the US-led invasion toppled the hardline Taliban regime in late 2001.
"Up to eight US drones fired some 18 missiles at multiple militant targets in Dattakhel village," a senior security official said. "At least 16 militants were killed in the missile strikes."
Local administration and intelligence officials confirmed the deaths after the missile barrage reportedly struck militant hideouts and a training centre in three places in the village.
Residents of Miranshah, the main town in the North Waziristan tribal district, said they saw the drones flying overhead and heard the explosions from Dattakhel, 40 kilometres west of the town.
Drone bombings have soared recently as US President Barack Obama puts Pakistan at the heart of his administration's fight against Al-Qaeda and Islamist extremists. More than 700 people have been killed in such strikes since August 2008.
The Pakistani government publicly condemns the strikes, which fuel anti-American sentiment in Muslim Pakistan, but US officials say they are necessary to protect foreign soldiers stationed in Afghanistan and have killed a number of high-value extremists.
Pakistani Taliban leader Hakimullah Mehsud has been a prime target of the drone attacks and reports are swirling that he died of injuries sustained in a January strike on the Taliban stronghold of North Waziristan.
The Taliban however flatly deny that he is dead and Mehsud has purportedly issued audio tapes saying he is alive and well.
Mehsud assumed leadership of the Tehreek-e-Taliban Pakistan (TTP), blamed for the deaths of thousands of people in attacks, after his predecessor, Baitullah Mehsud, was killed in a US drone strike in August last year.
He claimed responsibility for a December suicide bombing on the CIA at a US base in Afghanistan -- the deadliest attack on the US spy agency in 26 years.
Washington is also pressing Islamabad to tackle militants in the northwest who use Pakistan soil to launch attacks in Afghanistan, where about 113,000 troops under US and NATO command are battling a Taliban-led insurgency.
A Pakistani military commander said a new air and ground offensive had killed up to 80 militants Tuesday in the northern extremity of the semi-autonomous tribal belt, considered by Washington to be the most dangerous place on the planet.
The paramilitary Frontier Corps stepped up an offensive targeting Taliban havens in Bajaur district after a suicide bombing killed 17 people at a military checkpoint on Saturday.
The raids were concentrated around Mamoond, about 12 kilometres north-west of Khar, a notorious Taliban hideout which Pakistan failed to clear in past offensives against militant havens.
"When we started the operation, it was estimated that there were about 1,000 militants present in the area and 80 of them have been killed so far," Colonel Rana Munnawar told reporters in the village of Sawai.
There was no independent confirmation of the toll.
Munnawar claimed the offensive had dislodged a Taliban command and control system, but expected main operations to take another 15 days.
Pakistan first launched offensives in the district in August 2008 and has claimed several times to have eliminated the Islamist militant threat there.
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