Guinea-Bissau's President Malam Bacai Sanha has died in hospital in Paris, according to a statement from his office read over national radio.
The 64-year-old had travelled to France for medical treatment in late November after being taken seriously ill.
Mr Sanha was elected president in 2009 after years of unrest and coups.
Last month the United States warned its citizens in Guinea-Bissau that there was increased potential for political instability and civil unrest there.
The nature of the president's illness has not been made public but he was thought to suffer from diabetes.
Mr Sanha had previously been in intensive care in neighbouring Senegal.
The statement from Mr Sanha's office announced "with pain and sadness" that he died at the Val-de-Grace military hospital in Paris where he had been receiving treatment.
He had frequently been hospitalised abroad since being elected Guinea-Bissau's leader. A French official told news agencies that the president had been in a coma prior to his death.
The West African country has endured repeated coups and unrest since independence from Portugal in 1974, and has become a hub for drug trafficking between Latin America and Europe.
Correspondents say large parts of the political and military establishments have been corrupted by drugs money.
In late December the head of the navy, Jose Americo Bubo Na Tchuto, who has been accused by the United States of being involved with cocaine smuggling, tried to take over a military barracks in what appeared to be a failed coup attempt.
Mr Sanha's predecessor as president, Joao Bernardo Vieira, was assassinated by mutinous soldiers.
A reconciliation conference had been scheduled for this week between various political and military groups, but was postponed because of the president's absence. The recently appointed British mediator to Guinea-Bissau, Ian Paisley Junior MP, says Mr Sanha's death makes the convening of the conference all the more urgent.
Under Guinea-Bissau's constitution, the speaker of parliament, Raimundo Pereira, should now be sworn in as interim president.
Mr Sanha was a veteran of Guinea-Bissau's independence war and had long-standing ties to the ruling party, the left-wing African Party for the Independence of Guinea and Cape Verde (PAIGC).
He had previously served as interim president and had made two unsuccessful bids for the presidency, in 2000 and in 2005, before winning elections in July 2009.
He was married, with one child.