US missiles killed 15 militants in Pakistan's Taliban and Al-Qaeda stronghold of North Waziristan on Monday.
The attack looked set to inflame tensions with Islamabad ahead of a visit by a US assistant defence secretary, Peter Lavoy, on a mission to persuade Pakistan to end a six-month blockade on NATO supplies crossing into Afghanistan.
There has been a dramatic increase in US drone strikes in Pakistan since a NATO summit in Chicago ended two weeks ago without a deal on the NATO supply lines.
Eight drone strikes have been reported in Pakistan since May 23, the same number as in the previous four months, and Monday's was the deadliest since 18 Pakistani Taliban were reported killed on November 16, 2011.
Pakistani officials said two missiles slammed into a compound in the village of Hesokhel, east of Miranshah, the capital of North Waziristan, before dawn.
North Waziristan is Pakistan's premier hotbed of Islamist militants and where Islamabad has rejected US pressure to wage a major ground offensive against militants active in the 10-year war against US troops in Afghanistan.
"Fifteen militants were killed in a dawn strike on a compound. The bodies of those killed were unable to be identified," a security official in Miranshah told AFP.
He said there were unconfirmed reports that foreigners were among the dead.
Local resident Gul Jaan Wazir told AFP that the dead bodies were quickly buried after being pulled out of the rubble. The drone strike destroyed the room in the mud and wooden house where they had all been sleeping, Wazir said.
In the debris, local people found letterheads of Tehreek-e-Taliban Pakistan, the country's main umbrella Taliban faction waging an insurgency against the Pakistani government, wooden beds, blankets and mattresses.
Washington considers Pakistan's semi-autonomous northwestern tribal belt the main hub of Taliban and Al-Qaeda militants plotting attacks on the West and in Afghanistan.
Distrust over Pakistan's refusal to do more to eliminate the Islamist threat has become a major thorn in increasingly dire Pakistani-US relations.
Both sides are at loggerheads over reopening NATO supply lines that Pakistan shut in fury on November 26 when US air strikes killed 24 Pakistani soldiers.
Negotiations have snagged over costings, with American officials refusing to pay the thousands of dollars per container that Pakistan has reportedly demanded.
Islamabad initially conditioned reopening the lines on an American apology for the deaths of the 24 soldiers and an end to drone strikes, but neither is likely to happen.
Instead, Lavoy will fly into Islamabad this week in an attempt to break the deadlock, a Pakistani government official told AFP.
"Talks will focus on re-opening the NATO supply route, ways to promote border coordination and settle the issue of the Coalition Support Fund (CSF)," he said.
From 2002 to 2011, the United States paid Pakistan $8.8 billion for its efforts to fight militancy under the CSF, but Islamabad stopped claiming the money after US troops shot dead Osama bin Laden in Pakistan in May 2011.
Analysts now say, however, that Islamabad desperately needs the money with a budget deficit looming out of control and a general election widely believed to be months away.
Pakistani authorities whipped up anti-American sentiment after the bin Laden raid and are increasingly vocal in their belief that drone strikes violate national sovereignty.
But US officials consider the attacks a vital weapon in the war against Islamist extremists, despite concerns from rights activists over civilian casualties.
The London-based Bureau of Investigative Journalism has said that under President Barack Obama one drone strike has hit Pakistan on average every four days.
It said most of the 2,292 to 2,863 people reported to have died were low-ranking militants, but that only 126 fighters had been named.
It said it had credible reports of 385 to 775 civilians being killed, including 164 to 168 children.