The drone fired two missiles at a home in Azam Warsak area of South Waziristan Agency, officials said. Five suspected Taliban rebels were killed and seven injured in the attack.
Details of those killed and injured were not immediately available.
Local residents said drones continued hovering over the area after the missile strike.
This was the first drone strike in Pakistan's tribal belt since February 24, when four suspected militants were killed by a pilotless plane in the restive North Waziristan Agency.
The CIA resumed drone strikes in the tribal belt in February after a lull of almost a month in the wake of the arrest of suspected security contractor Raymond Davis in Lahore.
There has been speculation that the US had put drone strikes on hold to curb rising anti-American sentiments in Pakistan as it worked for the release of Davis.
Davis was arrested in Lahore on January 27 after he shot and killed two armed men.
The last strike before Davis' arrest was carried out on January 23.