Ann Patchett, who won the Orange Prize for Fiction for female writers in 2002, was nominated again on Tuesday with "State of Wonder", her sixth novel.
She was one of three U.S. authors on a shortlist of six, including Cynthia Ozick, who turned 84 on Tuesday and was the oldest nominee for the annual award.
"My only regret is that the rules of the prize don't permit a longer shortlist," said author Joanna Trollope, chair of the judges. "However, I am confident that the 14 novels we had to leave out will make their own well-deserved way."
The winner of the prize, which comes with a cheque for 30,000 pounds ($48,000), will be announced in London on May 30.
Patchett won the award 10 years ago with "Bel Canto", and in 2012 is in the running with State of Wonder, described by organisers as a journey into the "heart of the South American darkness".
It follows Marina Singh as she tries to track down enigmatic scientist Annick Swenson in the Amazonian rainforest, where she is developing a drug that could alter women's lives forever but refuses to report on her progress.
Ozick's contender, "Foreign Bodies", revolves around Bea Nightingale, another woman who leaves her familiar surroundings to travel from the United States to France where she becomes entangled in the lives of her brother's family.
The third U.S. author, Madeline Miller, was nominated for her debut novel "The Song of Achilles", based on Greek legend, which she worked on for 10 years.
Ireland's Anne Enright, the Man Booker Prize winner in 2007, was shortlisted for "The Forgotten Waltz", about love and desire set in modern-day Dublin, and Britain's Georgina Harding was nominated for "Painter of Silence" set in 1950s Romania.
Canadian writer Esi Edugyan rounded out the 2012 nominees with "Half Blood Blues", which takes place in Paris in 1940 and Berlin 50 years later. (Reporting by Mike Collett-White, editing by Paul Casciato)