The strike took place in Ghwakhwa area, 10 kilometres west of Wana, the main town of South Waziristan tribal region, where the military launched an operation two years ago.
"A US drone fired three missiles on a militant compound, killing five rebels," a senior security official in the area told AFP.
Another security official confirmed the strike and casualties but said the identities of those killed in the attack were not immediately known.
Friday's attack was the ninth to be reported in Pakistan's tribal areas, close to the Afghan border, since US commandos killed terror mastermind Osama bin Laden in a raid in the Pakistani city of Abbottabad on May 2.
The Pakistani parliament has called for an end to US drone strikes and said there must be no repeat of the operation that killed bin Laden, despite the fact that President Barack Obama has reserved the right to act again.
The drone strikes are hugely unpopular among the general public, who are deeply opposed to the government's alliance with Washington, and inflame anti-US feeling, which has heightened further after the Bin Laden raid.
But US officials insist that the missile strikes have severely weakened Al-Qaeda's leadership and killed high-value targets including the former Pakistani Taliban chief Baitullah Mehsud.
Missile attacks doubled in the area last year, with more than 100 drone strikes killing over 670 people in 2010, compared with 45 strikes that killed 420 in 2009, according to an AFP tally.
Most of the attacks have been concentrated in North Waziristan, the most notorious Afghan Taliban and Al-Qaeda bastion in Pakistan, where the United States wants the Pakistan military to launch a ground offensive as soon as possible.
But Lieutenant General Asif Yasin Malik, the commander supervising all military operations in Khyber Pakhtunkhwa province, told reporters on Wednesday "We will undertake operation in North Waziristan when we want to. We will undertake such an operation when it is in our national interest militarily," the general said, describing North Waziristan as calm and peaceful as it was weeks ago.
The strike comes hours after Finance Minister Hafeez Sheikh presented the 2011-12 budget in Parliament amidst harsh criticism from the opposition.
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