He was 83.
Spitzer died of heart problems, said his wife, Columbia University Professor Emerita Janet Williams.
Dr Spitzer's work on several editions of the Diagnostic and Statistical Manual of Mental Disorders, or the DSM, defined all of the major disorders "so all in the profession could agree on what they were seeing," said Williams, who worked with him on DSM-III, which was published in 1980 and became a best-selling book.
"That was a major breakthrough in the profession," she said.
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"Rather than just appealing to authority, the authority of Freud, the appeal was: Are there studies? What evidence is there?" Spitzer told the New Yorker magazine in 2005. "The people I appointed had all made a commitment to be guided by data."
Dr Allen Frances, a professor emeritus of psychiatry at Duke University and editor of a later edition of the manual, told the Times that Spitzer "was by far the most influential psychiatrist of his time."
He decided to push for the change after he met with gay activists and determined that homosexuality could not be a disorder if gay people were comfortable with their sexuality.
At the time of the psychiatric profession's debate over homosexuality, Dr Spitzer told the Washington Post: "A medical disorder either had to be associated with subjective distress pain or general impairment in social function."
Dr Jack Drescher, a gay psychoanalyst in New York, told the Times that Spitzer's successful push to remove homosexuality from the list of disorders was a major advance for gay rights.