The CIA-operated spy plane fired two missiles at the compound in Datta Khel area near the Afghan border.
TV news channels quoted their sources as saying that 21 people were killed. Foreign fighters were among the dead.
The strike destroyed the compound, witnesses said.
Datta Khel is considered a stronghold of Hafiz Gul Bahadur, the commander of a Taliban faction accused of sending fighters across the border to fight foreign troops in Afghanistan.
This was the first US drone strike since Pakistan restored supply lines for NATO troops in Afghanistan on Tuesday.
It was also the second drone strike in North Waziristan Agency in a week.
A US drone killed eight persons in Shawal area on July 1.
Today's strike came days after Pakistani leaders said talks were continuing with the US on ending the drone campaign following the reopening of NATO supply routes.
The Foreign Office said on Thursday that the US drone attacks were counter-productive and a violation of Pakistan's sovereignty.
The US has rejected calls from Pakistan to stop the drone strikes, insisting that the spy planes are effective in eliminating Al Qaida and Taliban elements hiding in the tribal belt.