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Sept. 11, 2012: A protester reacts as the U.S. Consulate in Benghazi is seen in flames during a protest by an armed group.

Former Secretary of State Hillary Clinton has called the Benghazi terrorist attack -- which killed Ambassador Chris Stevens, foreign service officer Sean Smith, and CIA contractors Ty Woods and Glenn Doherty -- the most significant failure on her watch.

In a question and answer session at Simmons College Wednesday night, Clinton listed the terrorist assault on the diplomatic compound in eastern Libya as her biggest regret.

"It would certainly be the attack on our facility in Benghazi, and the loss of, uh, two State Department personnel and two CIA contractors from the terrorist attack and the terrible consequences of that," she said.

"It's very, very painful and it was certainly the biggest regret that I had as Secretary of State."

While Benghazi's impact on a possible presidential run is unknown, Clinton focused on the emotional toll.

"They weren't the only people that we lost, but we lost them in such a terrible, senseless, terrorist action that, you know, it's just deeply sorrowful and it went on for hours, because the CIA annex was attacked after the State Department facility was attacked," she said of the Sep. 11, 2012 assault.

Her comments stand in sharp contrast to her defiant congressional testimony in January 2013, when she appeared before the Senate Foreign Affairs Committee.

"The fact is we had four dead Americans, was it because of a protest or was it because of guys out for a walk one night who decided that they'd they go kill some Americans? What difference at this point does it make?" she asked.

Those who have followed Benghazi from the day of the attack, including national security correspondent Eli Lake of the Daily Beast, said it was a significant change in tone.

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Clinton calls Benghazi terror attack 'biggest regret' on her watch