American officials have long said that al-Qaida mastermind Osama bin Laden and senior lieutenants of the network accused in the Sept. 11 attacks operate out of the rugged terrain along the border with Afghanistan.
But Clinton's unusually blunt comments went further in asserting that Pakistan's government has done too little about it.
"I find it hard to believe that nobody in your government knows where they are and couldn't get them if they really wanted to," Clinton said in an interview with Pakistani journalists in Lahore. "Maybe that's the case. Maybe they're not gettable. I don't know."
There was no immediate reaction from Pakistani officials, but the thrust of Clinton's comments were startling, coming after months of lavish public comments from her and other American officials portraying Pakistan's leaders as finally receptive to the war against militants inside their own country.
As a political spouse, career public official and recently as a diplomat, Clinton has long showed a tendency toward bluntness, sometimes followed by a softening of her comments. But her remarks about Pakistan's lack of action against al-Qaida comes at a particularly sensitive moment - amid a major Pakistani offensive against militants and a deadly spate of insurgent violence.
Clinton on Friday was wrapping up her three-day visit to Pakistan with a series of interviews with Pakistani journalists - including a session with women journalists that was to be broadcast live - and talks with leaders of Parliament. Then she was to fly to the Persian Gulf city of Abu Dhabi for meetings with Palestinian President Mahmoud Abbas, to be followed over the weekend by a meeting in Israel with Prime Minister Benjamin Netanyahu.
With Pakistan reeling from Wednesday's devastating bombing that killed more than 100 people in Peshawar, Clinton also engaged in an intense give-and-take with students at the Government College of Lahore. She insisted that inaction by the government would have ceded ground to terrorists.
"If you want to see your territory shrink, that's your choice," she said, adding that she believed it would be a bad choice.
Richard Holbrooke, the special U.S. representative on Afghanistan and Pakistan, told reporters that Clinton planned to meet late Thursday with the army chief, Gen. Ashfaq Parvez Kayani, to get an update on the offensive that began Oct. 17 against Taliban forces in a portion of the tribal areas near the Afghan border.
"We want to encourage them," Holbrooke said of the Pakistanis. "She wants to get a firsthand account of the military situation."
During her exchange with the Pakistani journalists, one reporter asked Clinton why the fight against terrorism seemed to put Pakistan at the center and why other countries couldn't do more. Clinton noted that al-Qaida has launched attacks on Indonesia, the Philippines and many other countries over the years.
"So the world has an interest in seeing the capture and killing of the people who are the masterminds of this terrorist syndicate. As far as we know, they are in Pakistan."
On Clinton's flight to Islamabad after the interview with Pakistani journalists, U.S. Ambassador Anne Patterson said Clinton's remarks approximate what the Obama administration has told Pakistani officials in private.
"We often say, `Yes, there needs to be more focus on finding these leaders,"' Patterson said. "The other thing is, they lost control of much of this territory in recent years, and that's why they're in South Waziristan right now."
In Lahore, dozens of students rushed to line up for the microphone when the session with Clinton began. Their questions were not hostile, but showed a strong sense of doubt that the U.S. could be a reliable and trusted partner for Pakistan.
One woman asked whether the U.S. could be expected to commit long term in Afghanistan after abandoning the country after Russian occupiers retreated in 1989.
"What guarantee," the woman asked, "can Americans give Pakistan that we can now trust you - not you but, like, the Americans this time - of your sincerity and that you guys are not going to betray us like the Americans did in the past when they wanted to destabilize the Russians?"
Clinton responded that the question was a "fair criticism" and that the U.S. did not follow through in the way it should have. "It's difficult to go forward if we're always looking in the rearview mirror," said Clinton, on the second of a three-day visit, her first to Pakistan as secretary of state.
The Peshawar bombing in a market crowded with women and children appeared timed to overshadow her arrival. It was the deadliest attack in Pakistan since 2007.
She likened Pakistan's situation - with Taliban forces taking over substantial swaths of land in the Swat valley and in areas along the Afghan border - to a theoretical advance of terrorists into the United States from across the Canadian border.
It would be unthinkable, she said, for the U.S. government to decide, "Let them have Washington (state)" first, then Montana, then the sparsely populated Dakotas, because those states are far from the major centers of population and power on the East Coast.
Clinton was responding to a student who suggested that Washington was forcing Pakistan to use military force on its own territory.
During her hourlong appearance at the college, Clinton stressed that a key purpose of her trip was to reach out to ordinary Pakistanis and urge a better effort to bridge differences and improve mutual understanding.
But her tough comments about Pakistan's will to take on al-Qaida leaders might not sit well among Pakistanis who long have complained about American demands on their country.
Clinton has ruffled feathers before with blunt comments during international trips. On her first visit to Asia in February, she discussed the possibility of a succession crisis in North Korea and suggested the U.S. would not press China that hard on human rights.
On a later trip, she drew criticism from Israeli leaders for talking about a "defense umbrella" for Arab Gulf states to protect them from a potential nuclear threat from Iran.
Despite her comments during the town hall event in Lahore, Clinton declined to touch on the sensitive issue of missile attacks from U.S. drones against militants inside Pakistan.
The subject has stirred some of the strongest feelings of anti-Americanism in the country, but the U.S. routinely refuses to acknowledge publicly that the attacks are taking place.
"There is a war going on," Clinton said, adding only that the U.S. wants to help Pakistan be successful.
The United States has provided Pakistani commanders with video images and target information from its military drones as the army pushes its ground offensive in Waziristan, U.S. officials said this week.
The U.S. in recent months has rushed helicopters and other military equipment to the country as Islamabad began offensives.
"We've put military assistance to Pakistan on a wartime footing," Lt. Col. Mark Wright, a Pentagon spokesman, said Thursday.
Associated Press writers Tim Sullivan in Islamabad, and Pauline Jelinek and Matthew Lee in Washington contributed to this report.