The strike took place in Landidog village, 20 kilometres west of Wana, the main town in South Waziristan tribal region.
"A US drone fired two missiles targeting a compound, killing five militants," a senior Pakistani security official told AFP.
He said that militants were using the compound owned by a local tribesman named as Fazal Karam.
Another security official confirmed the attack and casualties but said the "identities of those killed in the strike were not yet known".
It was not immediately clear if there were any high-profile victims in the latest drone strike on the tribal areas, which are close to the Afghan border and a key battleground in the fight against the Taliban and al Qaeda.
Missile attacks doubled in the tribal areas last year as the covert campaign was stepped up, 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.
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