The keyboardist and singer, 59, had been in a coma since last November 21. Preston died at Shea Scottsdale Hospital in Scottsdale, Arizona.
Preston was often called the fifth Beatle because he played the keyboard for the albums Let it Be, The White Album, and Abbey Road.
Preston also played on the Miss You disc from the Rolling Stones, and performed with Eric Clapton, Sly & The Family Stone, and Joe Cocker. His career began in the 1960s when he toured with Little Richard in Europe.
The musician was also known to have many personal problems. In 1992, he spent nine months in a drug rehabilitation centre. Five years later, he spent three years behind bars for a parole violation. In 1998, he plead guilty to accusations of insurance fraud.