The White House has said it "welcomes the demise" of al-Qaeda number three and Afghan operations chief Mustafa Abu al-Yazid.
US officials say they believe he was killed recently in the tribal areas of Pakistan in an American drone attack.
Mr Yazid, also known as Sheikh Said al-Masri, died along with his wife and three children, Islamist websites said, quoting a statement from al-Qaeda.
White House spokesman Robert Gibbs said it was "a severe blow" to al-Qaeda.
Mr Gibbs said Mr Yazid was one of the biggest targets to have been killed or captured in five years.
American officials often refer to the Egyptian-born militant as the main conduit to al-Qaeda leader Osama Bin Laden.
As al-Qaeda's operational commander in Afghanistan, Mr Yazid is believed to have had a hand in everything from finances to operational planning.
A US official, speaking on condition of anonymity, said there was "strong reason" to believe that Mr Yazid was killed in Pakistan's tribal areas in the past two weeks.
US monitoring groups said a message from al-Qaeda posted on Islamist forums on 31 May said the militant's wife, three of his daughters, his granddaughter, and other men, women, and children were killed.
The message translated by the SITE group, which monitors Islamist websites, did not give any details about the circumstances of his reported death, other than to speak of his "martyrdom".
"His death will only be a severe curse by his life upon the infidels. The response is near. That is sufficient," said the message translated by SITE.
Previous reports of his death have been incorrect, but this is the first time al-Qaeda has acknowledged such claims.
Mr Yazid is thought to have climbed to the number three position in al-Qaeda in 2007, when his predecessor, Abu Ubaida al-Masri, died of hepatitis in Pakistan.
He is reported to have managed the finances for the 11 September 2001 attacks in New York and Washington.
In a rare interview with Pakistan's Geo TV in 2008, he said al-Qaeda was "properly involved" in those attacks, as well as the 1998 attacks on US embassies in Kenya and Tanzania.
He also denounced the Pakistani government for fighting Islamic militants, justified suicide attacks, and predicted victory for Taliban and al-Qaeda forces in Afghanistan.
He is believed to have been jailed in Egypt in 1982 in connection with the assassination of Egypt's then-President Anwar Sadat.
Mr Yazid's last public statement was released on 4 May, eulogising the two top al-Qaeda leaders in Iraq - Abu Omar al-Baghdadi and Abu Ayub al-Masri - who were killed in April.