Veteran US diplomat Richard Holbrooke has died following a second round of surgery to treat a torn aorta.
Mr Holbrooke was best-known for helping to broker the Dayton Peace agreement in 1995 which ended the Bosnian war.
At the time of death he was President Barack Obama's special envoy to Afghanistan and Pakistan.
Mr Obama called the 69-year-old, who was known for bringing warring leaders to the negotiating table, a "true giant of American foreign policy".
Mr Holbrooke was meeting Secretary of State Hillary Clinton at the US state department on Friday morning when he collapsed.
He was rushed to the US capital's George Washington University Hospital, where he underwent a 21-hour operation to repair a tear in his aorta - the largest artery in the human body, which carries oxygenated blood from the heart.
Mr Holbrooke's death comes as the Obama administration prepares to make public its latest review of US policy in Afghanistan and Pakistan later this week.
'Foreign policy giant'
Mr Holbrooke was focused on the challenges in the region until his final breath, according to reports.
As the veteran diplomat was led into surgery, he is reported to have turned to the Pakistani surgeon at his side and appealed for an end to the war in Afghanistan.
Following the news of his death, Mr Obama said: "Michelle and I are deeply saddened by the passing of Richard Holbrooke, a true giant of American foreign policy who has made America stronger, safer and more respected.
"He was a truly unique figure who will be remembered for his tireless diplomacy, love of country, and pursuit of peace."
Mrs Clinton also paid tribute to Mr Holbrooke's service, saying the US had lost "one of its fiercest champions and most dedicated public servants".
"He was one of a kind - a true statesman - and that makes his passing all the more painful," she said in a statement.
Beginning with a foreign service posting in Vietnam in 1962, the veteran diplomat served under every Democratic president from John F Kennedy to Mr Obama.
But it was his role in Europe, helping bring to an end the war in Bosnia, that solidified his reputation as an important figure in foreign policy.
Nicknamed the Bulldozer, the veteran diplomat once said he had no qualms about "negotiating with people who do immoral things", if it served efforts for peace.
Mr Holbrooke was named by Mr Obama as his special representative to Afghanistan and Pakistan shortly after the president took office in January 2009.
Since moving into that position under the Obama administration, he had led the difficult task of pushing Kabul and Islamabad to work together against al-Qaeda and Taliban militants.
The bruising style that served him elsewhere ruffled feathers in Pakistan, says the BBC's Orla Guerin in Islamabad. There was a sense, especially earlier on, that a more nuanced and subtle approach was needed.
But officials spoke of a "huge vacuum" left by his passing.
President Asif Ali Zardari said Mr Holbrooke had been a friend to the nation, and a friend to him. He said the best response to his death would be to recommit to the fight against militancy.
Afghan President Hamid Karzai said Mr Holbrooke was "a veteran and seasoned diplomat who had served greatly the government and the people of the United States".
Mr Holbrooke, a New York City native, also served as the US ambassador to the United Nations and to Germany, as well as the assistant secretary of state.
Analysts had said the veteran diplomat could one day serve as a future secretary of state.
Mr Holbrooke's deputy, Frank Ruggiero, is expected to stand in for him in the interim.