The CIA-operated spy plane targeted a house in Chashma Pul area of Miranshah, the main town of North Waziristan Agency, early this morning.
Four persons in the house were killed instantly and two others injured, TV news channels quoted officials as saying.
Local residents said several drones were seen hovering over the area after the attack.
The injured were taken to a nearby hospital, where officials described their condition as critical.
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This was the first drone strike in Pakistan since the May 11 polls and the announcement of a new policy for the use of the spy planes by President Barack Obama.
Pakistan's general election was won by the PML-N and Prime Minister-elect Nawaz Sharif, who is set to assume office in June, has said Washington must take Islamabad's concerns about drone strikes seriously.
US and Afghan officials describe North Waziristan as a safe haven for Taliban and Al Qaeda elements and many top militant commanders have been killed by US drones in the region.