Omar Suleiman, who for years headed Egyptian intelligence under ousted President Hosni Mubarak, has died in the USA.
He died in hospital in the early hours of Thursday, the official news agency Mena reported.
Gen Suleiman, who was in his seventies, was appointed vice-president by Mubarak in the last days of his rule.
He made a bid to stand for president in this year's election but was disqualified for technical reasons.
Correspondents say he was seen as an enigmatic figure both inside and outside Egypt, and played a behind-the-scenes role in issues such as relations with the US and Israel.
In a statement, Egypt's interim government paid tribute to Suleiman, calling him a "patriotic, honest figure".
An assistant to Gen Suleiman said his death was unexpected.
"He was fine. It came suddenly while he was having medical tests in Cleveland," Hussein Kamal told Reuters news agency, adding that preparations were under way to take the body home for burial.
Reem Mamdouh, a member of Suleiman's presidential campaign team, told AFP that the general's health had been declining.
"His health deteriorated recently. He was in the United States with his family," he said.
State news agency Mena quoted a diplomat as saying he had been suffering from lung disease and had also developed heart problems.
Gen Suleiman headed the Egyptian General Intelligence Services (Egis) for 18 years.
He became the country's first vice-president in 30 years on 29 January 2011, four days after the popular uprising against Mubarak began.
Two weeks later, he appeared on state television to announce the long-time president had stepped down, prompting celebrations in Cairo's Tahrir Square - the focus of Egypt's protest movement.
After failing to win enough signatures to stand in Egypt's first post-Mubarak presidential vote earlier this year, he left the country, reportedly going to Abu Dhabi, then to Germany, then finally to the US for treatment.
The BBC's Jon Leyne in Cairo says Omar Suleiman was a key figure behind the presidency of Hosni Mubarak.
As spy chief, Gen Suleiman helped enforce the police state that kept Mubarak in power, he says.
He is believed to have indirectly saved Mubarak's life, advising him to take an armoured car on a state visit to Ethiopia in 1995 - his convoy was ambushed by Islamists.