The attack on Chashma village near Miranshah, the main town of lawless North Waziristan district, a stronghold of Taliban and Al Qaeda-linked militants on the Afghan border, wounded two others, officials said.
Security sources said a senior Pakistani Taliban commander was among the dead, though his identity has not been confirmed.
"At least six militants have been killed and two wounded," one security official in Miranshah told AFP.
A second security official confirmed the death toll and told AFP that most of the dead bodies were badly mutilated.
A resident in Miranshah said he saw militants carrying six coffins in vehicles and sending them to Chashma village, some two kilometres (one mile) east of Miranshah.
Drone strikes have been unpopular in Pakistan, where the government publicly denounces them as illegal and a violation of sovereignty, but Washington believes they have been effective in wiping out Taliban and Al Qaeda leaders.
Obama last week defended the legality of the CIA-run strikes, which began in Pakistan in 2004 but became more frequent during his presidency, but outlined new rules for their use.
The guidelines say drone strikes can only be used to prevent imminent attacks, when the capture of a suspect is not feasible and if there is a "near certainty" that civilians will not be killed.
Responding to Obama's speech, the Pakistani foreign ministry repeated its long-held view that US drone strikes are illegal and counterproductive.
Leaked diplomatic cables and a television interview by former military ruler Pervez Musharraf have however indicated that Islamabad has privately approved the strikes in the past.
Wednesday's attack was also the first since Pakistan's May 11 general election, won by the Pakistan Muslim League-N (PML-N) of Nawaz Sharif.
Mr Sharif, due to assume office on June 5, has called the drone strikes a "challenge" to his country's sovereignty and said Washington must take Pakistani concerns seriously.
According to Britain's Bureau of Investigative Journalism, CIA drone attacks targeting suspected Al Qaeda and Taliban militants in Pakistan have killed up to 3,587 people since 2004, including up to 884 civilians.
The frequency of drone strikes in Pakistan has tailed off in recent months, the last coming on April 17.
On Sunday US Secretary of State John Kerry said this was because the tactic had "been so successful in rooting out Al Qaeda in Pakistan" and was only used after targets were confirmed "at the highest levels".