The CIA-operated spy plane targeted a house in Chashma Pul area of Miranshah, the main town of North Waziristan Agency, early Wednesday 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.
The identity of the dead and injured could not immediately be ascertained.
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.
Pakistan's Foreign Secretary Jalil Abbas Jilani said on Friday that the drone strikes were illegal and counter-productive despite the new guidelines unveiled by Obama.
Nawaz Sharif is back, but what does it mean for India?
Wal-Mart to pay $110 mn for environmental crimes
Pakistan releases 45 Indian fishermen
Why schools are off limits for children in Waziristan
No impact on weapons system due to cyber hacking: US