The 88-year-old Perez's daughter, Maria Francia Perez, said her father had died in a Miami hospital.
"He was happy and well when he awoke this morning. Suddenly he had difficulty breathing," she told The Associated Press.
She said he was taken to a Miami hospital, where he died. She told the Venezuelan television channel Globovision he had died of a heart attack.
In the final years of his life, Perez came to personify the old guard Venezuelan political establishment bitterly opposed by current President Hugo Chavez. Perez survived two coup attempts in 1992, the first of which was led by Chavez, who was then a young army lieutenant colonel.
In recent years, Perez lived in Miami while the Venezuelan government demanded he be turned over to stand trail for his role in putting down bloody 1989 riots. Perez -- who governed Venezuela from 1974-79 and again from 1989-93 -- denied wrongdoing.
In his first term, he won praise by nationalizing Venezuela's oil industry, paying off foreign oil companies and then capitalizing on a period of prosperity that allowed his government to build subway lines, bankroll new social programs and set up state-run companies in areas from steel to electricity.
He became one of Latin America's most prominent political leaders, popularly known after his initials as "CAP."
Venezuelans elected him for a second time in 1988, hoping for a return to good times after a decade of economic decline. But his popularity plunged when he tried to push through an economic austerity program including increasing the subsidized prices of gasoline, and anger among the poor boiled over in the 1989 riots.
More than 300 people were killed in the unrest known as the "Caracazo." Some activists put the death toll much higher.
In 2010, Venezuela's Supreme Court cleared the way for Chavez's government to request Perez's extradition from the United States. Prosecutors accused Perez of ordering a harsh crackdown during the unrest, when rights activists say many were shot indiscriminately by security forces.
Perez stopped speaking in public after a 2003 stroke, but he maintained he was innocent. And his office issued a statement accusing the Supreme Court of doing Chavez's bidding after it approved plans for the extradition request.
The former president's supporters called the charges politically motivated. Members of his party Democratic Action announced in 2008 that Perez hoped to return to Venezuela and held talks with judicial officials on that possibility.
Party leader Henry Ramos Allup said the former president's condition was "extremely delicate" and that he hoped to "live out his last days in the country." But that possibility faded as government authorities called for his extradition.
While he was in office, Perez's popularity as a leader rose and fell with the country's economic situation, and he eventually came to be despised by many Venezuelans who resented his elegant suits and his affinity for jetting around Latin America.
Congress impeached Perez on corruption charges in 1993 and he was placed under house arrest. The Supreme Court convicted him in May 1996 of misspending $17 million in public funds -- a charge he always denied.
"I would have preferred another death," Perez said in his last speech as president, saying the accusations were politically motivated.
Part of the funds had been used to help bankroll the security detail of Violeta Chamorro before she was elected Nicaragua's president in 1990 over leftist incumbent Daniel Ortega. Perez defended that spending as legitimate to help ensure stability after years of conflict in Central America, where he had helped mediate in peace talks.
Perez spent more than two years under house arrest, then was released in September 1996.
Still admired by many Venezuelans, Perez was elected senator in 1998 for his home state of Tachira in the Venezuelan Andes.
After Chavez closed congress in 1999 to elect a new one under a new constitution, Perez left Venezuela. Starting in 2000, he spent his time in Miami, New York and the Dominican Republic, where he often condemned Chavez.
The Dominican government denied a request by Chavez in 2002 for Perez to be extradited to face more corruption charges. Chavez frequently accused Perez of coup plotting and in 2003 he temporarily cut oil supplies to the Dominican Republic. Both Perez and Dominican officials denied Chavez's charges.
On July 9, 2001, Perez left the Dominican Republic for cardiac tests in Miami. Even on his stretcher, he declared: "I promise the Venezuelan people that I am fighting to return total democracy."
He was hospitalized in October 2003 in New York after suffering a stroke. After that, he largely dropped out of the public eye.
Perez was born in the Andean border town of Rubio in 1922, one of 12 sons of a farmer and merchant. He married a first cousin, Blanca Rodriguez, with whom he had six children.
In later years, he had two children with his longtime mistress and secretary, Cecilia Matos, whom he married.
Perez began his political career in 1941 and quickly ascended the ranks of the Democratic Action party, one of two parties that governed the nation for 40 years after the fall of Gen. Marcos Perez Jimenez's dictatorship in 1959.
Under party leader and President Romulo Betancourt, Perez served as interior minister, fighting Cuban-backed guerrilla groups in the early 1960s.
Perez took over leadership of Democratic Action after Betancourt's death in 1981.
Troops loyal to Perez quashed two coup attempts, including the one led by Chavez in February 1992 and another led by rebel officers in November of that year. Chavez was jailed for two years and then was pardoned by President Rafael Antonio Caldera in 1994.
Even as Perez faced domestic troubles at home in his final years in power, he sought to play a statesman role internationally.
He helped promote talks to end wars in Central America in the 1980s, and when Haitian President Jean-Bertrand Aristide was ousted in 1991, he sent a plane for him. Then-U.S. President George H.W. Bush at the time called Perez one of the hemisphere's great democratic leaders.