Tragically, the agency thought it had its best chance last year at a secret base in Afghanistan, but instead fell victim to a double agent's devastating suicide bombing.
The CIA missed a chance to nab Ayman al-Zawahri in 2003 in the northwest Pakistani city of Peshawar, where he met with another senior al-Qaida leader who was apprehended the next day, several current and former U.S. intelligence officials said.
The fugitive Egyptian doctor may also have narrowly survived a bombing by Pakistani military planes in 2004, the former and current officials said. And a well-publicized U.S. missile strike aimed at him in 2006 failed because he did not turn up at the attack site, they said.
Targeting al-Zawahri - along with bin Laden - is a main goal of U.S. counterterror efforts, focused on a man who has retained control of al-Qaida's operations and strategic planning even as he has led an underground existence in Pakistan's rugged tribal border zone.
"Finding senior al-Qaida terrorists - at a time when we're pursuing the most aggressive counterterrorism operations in our history - is of course a top priority for the CIA," said agency spokesman George Little.
But unlike bin Laden, a cipher since the Sept. 11 attacks who has surfaced only in occasional taped statements, al-Zawahri has kept a higher public profile, taking risks that expose him more.
He is known to travel cautiously and regularly issues audio and video harangues that are scrutinized closely for clues, said the current and former officials, who insisted on anonymity to discuss the classified hunt for the al-Qaida leader.
The CIA's pursuit of al-Zawahri climaxed last December in the suicide bombing that left seven agency employees dead at the agency's eastern Afghanistan base in Khost, one of the worst U.S. intelligence debacles in recent decades.
The bomber turned out to be an al-Qaida double agent who had lulled U.S. intelligence into believing he could bring them closer to al-Zawahri. Part of the terrorist's bait was his claim that al-Zawahri suffered from diabetes - a revelation about his health, if true.
A blunt internal inquiry raked the CIA last month for failing to properly vet the double agent in the months before the bombing and suggested its preoccupation with al-Zawahri may have led to lapses in judgment. One person familiar with the inquiry said the agency's intent on getting to al-Zawahri was a "significant driver" behind the mistakes, a conclusion even CIA director Leon Panetta acknowledged.
"That's what this mission was all about," Panetta said. "It was the opportunity that we all thought we had to be able to go after No. 2." He added that "in some ways maybe the mission itself clouded some of the judgments that were made here."
Al-Zawahri has presented a more opportunistic target than bin Laden both because of his visibility and also because of the CIA's ability to develop better intelligence about his movements.
"We felt like we did at times come very close to getting him," said a former senior U.S. official familiar with the targeting efforts. "We had more of it (intelligence) and we had better confidence in it."
Former intelligence officials say both bin Laden and al-Zawahri take elaborate precautions, keeping their distance from each other to ensure that al-Qaida's top leadership would not be eliminated in a single strike.
Bin Laden, 53, is believed to be hiding near the border between Pakistan's lawless tribal regions and Afghanistan. Al-Zawahri, 59, appears to have spent time in Pakistan's northwest tribal region of Bajaur, populated by large numbers of Wahabi Islam followers.
Both men are believed wary of using cell or satellite phones. But al-Zawahri has tried at times to make contact with family members in Egypt, former intelligence officials say. More importantly, he has remained in the public eye with numerous messages.
According to the private SITE Intelligence Group, bin Laden has made 23 audio and one video tape since 2006. Al-Zawahri has outpaced his superior, making 37 audio and 22 video recordings in the same period. In al-Zawahri's latest audio recording, issued Nov. 4, he warned the U.S. that "we will fight you until the last hour."
Each time al-Zawahri speaks, he increases the chances the U.S. could zero in on him. The CIA scours his recordings for clues, the former officials said, sifting for signs that might indicate how long it takes al-Zawahri to receive information about current events he cites.
"It tells us about information flow," said Brian Fishman, a counterterrorism research fellow at the New America Foundation.
But despite the risks he takes, al-Zawahri has always been able to keep several steps ahead of his pursuers.
The CIA had its first chance on Feb. 28, 2003. Former intelligence officials say al-Zawahri met that day in a car with Khalid Sheikh Mohammed, the self-professed mastermind of the 9/11 attacks, in Peshawar. Al-Zawahri, a former official said, was on his way to the remote northern tribal region.
The former officials say the CIA was pursuing Mohammed at the time, but did not have a fix on him until an informant sent a text message to a CIA handler the next day that he was in Rawalpindi, about 110 miles to the east. Pakistan's spy service, which was working with the CIA, moved in and captured Mohammed.
By then, al-Zawahriwas gone.
Mohammed was flown to a CIA black site in Poland and interrogated using harsh methods, including waterboarding, which simulates drowning. Mohammed admitted he had met with al-Zawahribut would not disclose the details, a former CIA officer said.
The next chance to target al-Zawahricame in mid-March 2004, former officials said. A detainee in U.S. custody passed along information about a possible al-Qaida hideout in the mountainous northwest Pakistani region of South Waziristan, where government troops, helicopters and planes were mounting a military offensive against militants.
The CIA passed the intelligence to the Pakistan military, which bombed the village of Azam Warzak near the Afghan border. The former U.S. officials said they later received reports that al-Zawahriwas at the scene during the bombing and suffered minor injuries.
Pakistani military spokesman Gen. Athar Abbas would not confirm the reports, but noted recently that "these were the times when the two intelligence agencies were working hand in glove."
Taliban operatives and Pakistani civilians told AP recently that al-Zawahriwas injured in the attack. The al-Qaida leader then spent three days in the town of Mir Ali in north Waziristan before heading north to Bajaur, said the militants and locals, all who insisted on anonymity for safety reasons.
One key to locating al-Qaida's upper echelon, former U.S. officials said, is cracking the crude but effective communications network linking the fugitive terrorists. The system uses a chain of human couriers ensuring no one messenger interacts with either bin Laden or al-Zawahri.
A Taliban operative who filmed one of al-Zawahri's messages told AP that both bin Laden and al-Zawahri rely heavily on Arabs instead of locals for security. The operative insisted on anonymity for safety reasons. His role inside al-Qaida was confirmed by Afghan officials.
The CIA appeared to come close to cracking the network in May 2005, when Pakistani intelligence officials nabbed a high value detainee near Peshawar named Abu Faraj al-Libi. The suspect took command of the terror group's operations and communications after Mohammed's 2003 arrest.
The CIA had intelligence indicating the Libyan acted as "communications conduit," relaying messages from senior al-Qaida leaders to bin Laden. The former officials said al-Libi "almost certainly" had met with bin Laden or al-Zawahri after 9/11.
The day he was arrested, al-Libi was believed to be delivering a message to al-Zawahri. Taken to a black site in Romania, al-Libi gave up no information about al-Zawahri and bin Laden or how they traded messages, the former officials said.
"Libi seemed to be the key to the puzzle but it turned out he was a dead end," said Bruce Riedel, a senior fellow at the Brookings Institution Saban Center and a former CIA officer.
Despite his silence, the CIA thought it had another chance to target al-Zawahri on January 13, 2006. The CIA had received a tip their target was headed to a gathering of top al-Qaida operatives in the town of Damadola in the Bajaur region. Al-Zawahri reportedly had met with al-Libi a year earlier in Bajaur_ where locals had also pinpointed the terrorist leader after the 2004 bombing.
A former senior CIA official familiar with the episode said all the "intelligence signatures" pointed to al-Zawahri's arrival that day. Former CIA Director Porter Goss gave a green light to launch a drone missile strike, the former senior official said. Goss declined comment through a spokeswoman.
The drone strike obliterated a mud compound, killing eighteen people, provincial officials said, including several al-Qaida figures and a dozen civilians.
But al-Zawahri was not among them. Pakistani intelligence officials said at the time that he was invited to the dinner but decided instead to send several aides. The CIA initially thought the strike had missed the terrorist leader by an hour, but a current U.S. official recently acknowledged al-Zawahri never showed up.
Later that month after the strike, al-Zawahri taunted then-President George W. Bush in a videotape. "Bush," he said, "do you know where I am? I am among the Muslim masses."
The CIA thought it had its best chance yet to strike at al-Zawahri last year when a doctor working with Jordanian intelligence claimed to offer new details suggesting the terrorist leader suffered from diabetes. The former and current U.S. officials said there were already indications al-Zawahri might have the disease.
CIA officers began working with the informant, Humam al-Balawai, believing the doctor might gain access to al-Zawahri for medical reasons, the former officials said. When al-Balawi was taken to meet with CIA officials at a secret base in Khost, in eastern Afghanistan, last Dec. 30, the double agent detonated hidden explosives as the officials neared him.
Those familiar with the CIA's inquiry into the suicide bombing said the operation aimed at al-Zawahri ran afoul of one of the spy game's cardinal perils - wishfulness. In this case, the CIA was convinced it might finally have him in its sights after so many misses.
It proved to be one more miss, and a costly one.
Gannon reported from Kabul, Afghanistan, and Islamabad, Pakistan. Eileen Sullivan and Kimberly Dozier in Washington contributed to this report.