Duke was born in New York City, the only child of tobacco and hydroelectric power tycoon James Buchanan Duke and his second wife, Nanaline Holt Inman, widow of Dr. William Patterson Inman. At his death in 1925, the elder Duke's will bequeathed the majority of his estate to his wife and daughter, along with $17 million in two separate clauses of the will, to The Duke Endowment he had created in 1924. The total value of the estate was not disclosed, but was estimated variously at $60 million to $100 million (equivalent to $837 million to $1.395 billion in 2018), the majority culled from J.B. Duke's holds in Lucky Strike cigarettes. Duke spent her early childhood at Duke Farms, her father's 2,700-acre (11 km2) estate in Hillsborough Township, New Jersey.

Duke married twice, the first time in 1935 to James H. R. Cromwell, the son of Palm Beach society doyenne Eva Stotesbury. Cromwell, a New Deal advocate like his wife, used her fortune to finance his political career. In 1940 he served several months as U.S. Ambassador to Canada and ran unsuccessfully for the U.S. Senate. The couple had a daughter, Arden, who died one day after her birth. They divorced in 1943.  On September 1, 1947, while in Paris, Duke became the third wife of Porfirio Rubirosa, a diplomat from the Dominican Republic. She reportedly paid his second wife, actress Danielle Darrieux, $1 million to agree to an uncontested divorce. Because of her great wealth, Duke's marriage to Rubirosa attracted the attention of the U.S. State Department, which cautioned her against using her money to promote political agenda. Further, there was concern that in the event of her death, a foreign government could gain too much leverage. Therefore, Rubirosa had to sign a pre-nuptial agreement; during the marriage, though, she gave Rubirosa several million dollars in gifts, including a stable of polo ponies, sports cars, a converted B-25 bomber, and, in the divorce settlement, a 17th-century house in Paris. One of Doris Duke's best friends was Brazilian socialite and "jetsetter" Aimee de Heeren.  She reportedly had numerous affairs, with, among others, Duke Kahanamoku, Errol Flynn, Alec Cunningham-Reid, General George S. Patton, Joe Castro, and Louis Bromfield.  Duke posted a bail of $5,000,000 for her friend, former Philippine First Lady Imelda Marcos after the latter was arrested for racketeering.

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