The strike came as the US joint chief of staff chairman Admiral Mike Mullen arrived in Islamabad for discussions with the Pakistani military top brass.
Breaking a lull in attacks, US drones fired a volley of missiles at a terrorist compound in Pakistan's South Waziristan region, killing 18 militants including foreign fighters.
Sixteen militants were killed instantly while two more bodies were later pulled out of the rubble of the compound in the Angoor Adda area bordering Afghanistan, officials said.
At least five missiles were fired by several pilotless spy planes during a coordinated attack.
TV news channels said the death toll could rise.
The strike came as the US joint chief of staff chairman Admiral Mike Mullen arrived in Islamabad for discussions with the Pakistani military top brass.
The top most American commander has expressed US worries over Taliban and al-Qaeda sanctuaries in Pakistan and has urged the Pakistan army to strike against groups like the Haqqani network.
There was no immediate confirmation if any high-value target was among the casualties. US drones normally target key al-Qaeda and Taliban commanders.
There were conflicting reports over the nationalities of those killed. Some reports said they were all Pakistanis while others said foreign fighters were among the dead.
One of the reports said a Taliban commander named Maulana Halimullah escaped the attack unhurt.
The compound was being used by militants belonging to the Mullah Nazir group, which has so far not been targeted by the Pakistani security forces.
South Waziristan is a sanctuary for al-Qaeda and Taliban elements.
Soon after the attack, militants surrounded the area and forced residents to stay within their homes as they pulled the dead out of the rubble.
The Angoor Adda area, about 40km from Wana, the main town in South Waziristan, was repeatedly targeted by US drones last year.
South Waziristan was the scene of a major offensive by the Pakistan army last year.
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