Al Qaeda's number three, Sheikh Sa'ad Al-Masri, also known as Mustafa Abul Al-Yazid, was believed to have been killed in a similar strike in North Waziristan last month.
The latest attack targeted a sprawling compound used by the militants as a hideout in Norak, a village some 20 km (12 miles) east of the region's main town of Miranshah, an intelligence official said.
"According to initial reports three militants have been killed. Death toll may rise. We are checking," the officer based in Miranshah said. He said the identity of the slain militants could not be immediately ascertained.
Residents confirmed the incident, saying that smoke was rising from the site of the strike.
"Militants have cordoned off the area and no one is allowed to go near the site," villager Ahmed Shah told Reuters by telephone.
The United States stepped up missile strikes by pilotless aircraft into North Waziristan after a Jordanian suicide bomber attacked a US base across the border in Afghanistan's Khost province in late December, killing seven CIA employees.
The United States has long been pressing Pakistan to mount an offensive in North Waziristan, a known to be a haven for numerous militant groups, particularly Afghan Taleban who launch cross border attacks on Western forces in Afghanistan.
Pakistani officials say they are over-stretched and do not have enough resources to open another front while they consolidate gains from earlier offensives in neighboring South Waziristan and elsewhere in the northwest.
