Mr Holbrooke was meeting Ms Clinton at the US state department on Friday when he fell ill Veteran US diplomat Richard Holbrooke has died following a second round of surgery to treat a heart condition.
He fell ill on Friday while meeting US Secretary of State Hillary Clinton.
He was President Barack Obama’s special envoy to Afghanistan and Pakistan. The presidents of both nations had called to wish him well, prior to his death.
Nicknamed The Bulldozer, the 69-year-old gained a reputation over the years for confronting warring leaders to get them to come to the negotiating table.
Mr Holbrooke’s family was reported to be at his bedside earlier on Monday in the US capital’s George Washington University Hospital.
Mr Holbrooke was meeting Ms Clinton at the US state department on Friday morning when he collapsed.
He was rushed to hospital and had surgery to repair a tear in his aorta – the largest artery in the human body, which carries oxygenated blood from the heart.
President Barack Obama had praised Mr Holbrooke on Monday night at a holiday event at the state department, calling him a “tough son of a gun”.
“He is simply one of the giants of American foreign policy,” Mr Obama said.
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.
Mr Holbrooke was named by Mr Obama as his special representative to Afghanistan and Pakistan shortly after the president took office in January 2009.
He also served as the US ambassador to the United Nations and to Germany, as well as the assistant secretary of state.
BBC diplomatic correspondent Bridget Kendall says Mr Holbrooke was famous for his blunt speaking behind the scenes, despite his handshakes and careful courtesy in public.
Never afraid to bulldoze his way to a solution he got them all, Serb, Croat and Bosnian, to sign an accord in 1996, our correspondent says.
This article is from the BBC News website. © British Broadcasting Corporation, The BBC is not responsible for the content of external internet sites.