A CIA drone strike Monday targeted al-Qaeda's second in command, Abu Yahia al-Libi, in Pakistan, but it was unclear whether he was among those hit, US officials said.
US officials said fewer than five people were hit, although Pakistani officials say more than a dozen people were killed in two days of strikes in Pakistan.
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The CIA has carried out a half-dozen strikes in less than two weeks, as the US pushes ahead with the controversial drone program despite Pakistani demands that it stop.
US officials said they did not know yet whether al-Libi was among those killed, but said they were "optimistic."
Al-Libi would be the latest in the dozen-plus senior commanders removed in the clandestine US war against al-Qaeda since Navy SEALs killed Osama bin Laden last year.
The White House maintains a list of terrorist targets to be killed or captured, compiled by the military and the CIA and ultimately approved by the president.
The State Department's Rewards for Justice program had set a $1 million reward for information leading to the Libyan-born fugitive, who had filmed numerous propaganda videos urging attacks on US targets after he escaped a prison at Bagram Air Base in Afghanistan in 2005.
Al-Libi took the second-in-command spot when Egyptian-born Ayman al-Zawahri took charge of al-Qaeda after bin Laden's death. As al-Qaeda's de facto general manager, al-Libi is responsible for running the group's day-to-day operations in Pakistan's tribal areas and manages outreach to al-Qaeda's regional affiliates.
Al-Libi's death would be "another reason not to accept Pakistan's demand for an end to drone wars," added Brookings Institute's Bruce Riedel, a former CIA officer and adviser to the White House on Afghanistan and Pakistan policy.
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