Sheppard served ten years in the Ohio Penitentiary in Columbus for the murder of his wife before the U.S. Supreme Court ruled that the media had corrupted the original trial. A second trial in 1966 included pioneering work in crime scene investigation and blood evidence to prove Sheppard could not have killed Marilyn. Attorney F. Lee Bailey (1933–; see sidebar) won Sheppard's acquittal in 1967. A hostile press, however, continued to track Sheppard throughout his remaining years.
Sheppard's life became the inspiration for a popular television program called The Fugitive. In the television version, and a later movie version, the innocent doctor is accused of murdering his wife but escapes from prison and spends years on the run in search of the real killer. Both fictional and real life stories ended with the acquittal of the husband. Although in the film version the killer is apprehended, in the real-life Sheppard case the killer was never brought to justice.
Sheppard was finally a free man but he had lost his wife, and his son had been raised by his brother for over a decade. He tried to return to medicine in Ohio in 1968 but his skills had seriously deteriorated while he was in prison. The board at Youngstown Osteopathic Hospital restored Sheppard's surgical privileges but he was dismissed following several malpractice lawsuits. Dr. Sam Sheppard died of liver failure in 1970 at the age of forty-six.