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In 1914, beautiful Fanny Trellis is courted by many men including Jim Conderley, Ed Morrison and Thatcher. One evening, while her suitors wait downstairs, Fanny's cousin, George Trellis, returns home after several years away. George learns that contrary to their extravagant lifestyle, Fanny and her brother Trippy have no money. Trippy, however, now has a job working on Wall Street for Jewish Job Skeffington. Later that evening, Job calls unexpectedly for Trippy, who angrily refuses to see him.
At George's instigation, he and Fanny speak to Job instead. Job has fired Trippy for embezzling and has come to ask him to repay the stolen money. He is stunned when Fanny explains their financial situation. The next day, Trippy threatens to commit suicide. Determined to save her brother, Fanny sets her cap for Job and soon marries him, even though Job fully realizes that Fanny does not love him. Her ploy backfires, however, when an angry Trippy leaves for Europe, and that night, Fanny locks Job out of her room. Fanny's suitors are unfazed by her marriage and continue to pursue her. Job endures their presence because, although Fanny enjoys their attentions, she always sends them away.
On the night of the Skeffingtons' first anniversary, they learn that Trippy has joined the Lafayette Esquadrille and that Fanny is pregnant. Although Job is delighted by the coming child, Fanny sees it as a sign that she is growing old and insists on leaving for California until the baby is born and she is once again beautiful. Shortly after Fanny Junior is born, the U.S. enters the war. When Trippy is killed, Fanny blames Job for his death, and Job finally realizes that Fanny will never love him. After the war ends, Job devotes himself to his daughter, while Fanny occupies herself with a series of lovers. During prohibition, Fanny attracts a bootlegger named MacMahon, who is determined to marry her. To convince her to divorce Job, he demonstrates that Job has had several mistresses during their marriage. Although Fanny's rejection of her husband can be seen as partly responsible for his behavior, Job agrees to a divorce.
Not wanting to be bothered by a child, Fanny suggests that Job take custody of their daughter. Job is reluctant because of the difference in their religions and also because he plans to live in Europe, where the Fascists are coming to power. Fanny Junior's distress at losing her father, however, convinces Job to take her with him. Several years later, a middle-aged Fanny becomes involved with the much younger Johnny Mitchell, and Fanny Junior returns to the U.S. from Berlin. After sailing in stormy weather with Johnny, Fanny falls seriously ill with diphtheria. She recovers, but the illness ages her greatly, and she begins to hallucinate, imagining that she sees Job everywhere. A psychiatrist tells her the hallucinations are a subconscious manifestation of a need to see her former husband because, now that she is fifty, her romantic life is over.
Determined to prove him wrong, Fanny throws a dinner party for her old suitors, only to discover that they are all appalled by her aged appearance. Only Edward still seems smitten, but Fanny quickly realizes that he is only interested in her money. When Fanny Junior later announces that she and Johnny are getting married and moving to Seattle, Fanny is left totally alone. The next morning, George tells Fanny that he has seen Job, now a broken man after his stay in a concentration camp. George begs Fanny to care for Job in return for his generous care of her, but she refuses, believing that her lack of beauty will drive Job away as it did all the others. When she realizes that Job is blind, however, she knows that here is one man who will always remember her as beautiful and welcomes him home.