Cal Stephanides (his masculine identity), also known as Calliope (feminine), recounts how 5-alpha-reductase deficiency, a recessive condition, caused him to be born with female characteristics. The book continues with accounts of his family's history and the conception of Cal, his childhood and teenage years being raised as a girl, and the discovery of his intersex condition. Cal weaves his opinion of the events in hindsight from his life after his father's funeral. Middlesex is set in the 20th century and interjects historical elements, such as the Balkan Wars, the Nation of Islam, the 1967 Detroit riot, and the Watergate scandal into the story.
Cal's grandparents flee from Smyrna, boarding a passenger ship, as the city burns in flames.In 1922, Cal's paternal grandfather, Eleutherios "Lefty" Stephanides, lives in Bithynios, a village in Asia Minor. In the small village, high on the slope of Mount Olympos above the city of Bursa, incestuous marriages between cousins are a quietly accepted practice. Lefty makes a living selling silkworm cocoons harvested by his sister, Desdemona. The siblings are orphans; their parents are victims of the ongoing Greco-Turkish War. Lefty and Desdemona develop a romantic relationship as the war progresses. They flee the chaos brought by the war on a ship to the United States amid the Great Fire of Smyrna. Their histories unknown to the other passengers, they marry each other on board the vessel.
After arriving in New York, they locate and stay with their cousin Sourmelina "Lina" Zizmo, in Detroit, Michigan, a closeted lesbian and the only person who knows of the siblings' incestuous relationship. Lefty takes a job at Ford Motor Company, but is later retrenched. He unknowingly joins Lina's husband, Jimmy, in bootlegging. Desdemona gives birth to a son, Milton, and a daughter, Zoe. Lina gives birth to a daughter, Theodora or "Tessie". The relationship between Lefty and Desdemona declines after she learns that there is an increased chance of genetic disease for children born from incest. In 1924, after Milton's birth, Lefty opens a bar and gambling den called the Zebra Room.
Milton and Tessie marry in 1946. They have two children, Chapter Eleven[note 3] and Calliope ("Callie"). Prior to Callie's birth, Desdemona predicts the child to be a boy, although the parents prepare for a girl. Chapter Eleven is a biologically "normal" boy; however, Callie is intersex. Unaware of this, her family raise Callie as a girl. Elements of family life are portrayed against struggles in the rise and fall of industrial Detroit. The family gets caught up in the 1967 Detroit riot resulting from racial tensions, after President Johnson authorizes the use of federal troops, and the family restaurant is raided during this period. Fleeing school integration, the family moves to a house on Middlesex Boulevard, Grosse Pointe.
When she is 14 years old, Callie falls in love with her female best friend, whom Callie refers to as the "Obscure Object".[note 4] In separate encounters, Callie has her first sexual experiences with a woman, the Obscure Object, and with a man, the Obscure Object's brother. After Callie is injured by a tractor, a doctor discovers that she is intersex. She undergoes tests and examinations at a clinic in New York, and it is determined that her body will naturally develop more masculine traits. After learning about the syndrome and facing the prospect of sex reassignment surgery to make her anatomy appear "normally" female, Callie runs away and assumes a male identity as Cal, who hitchhikes cross-country and reaches San Francisco, where he joins a burlesque show as Hermaphroditus.
Cal is arrested by police during a raid on his workplace. He is released into Chapter Eleven's custody and learns of their father's recent death. The siblings return to their family home on Middlesex. Desdemona privately confesses to Cal that her husband is also her brother, recognizing Cal's condition and associating it with stories from her old village about children born of incest. As Milton's funeral takes place at the church, Cal stands in the doorway of his family home, assuming the male-only role in Greek traditions to keep his father's spirit from re-entering the home.[25]
Years later, Cal becomes a diplomat stationed in Berlin. He meets Julie Kikuchi, a Japanese-American woman, and tentatively starts a relationship with her after telling her about his past.[25]
