The iconic instrument bears the mark of characteristic cigarette burns and was the successor to his most famous guitar, a hybrid Stratocaster Clapton nicknamed ‘Blackie’.
The guitar up for sale, known as The Heir To Blackie, is being offered by the San Francisco Art Exchange with at a guide price of £247,000.
It was the first officially sanctioned Eric Clapton Signature Stratocaster and Clapton helped to design the guitar.
Clapton’s original beloved Blackie, which combined parts from three Fender Stratocasters made in the late fifties, was sold at auction to raise funds for the star’s Crossroads Centre Antigua alcohol and drug treatment centre.
It was bought by musical equipment retail chain Guitar Centre for nearly £750,000 to become the world’s most expensive guitar in 2004.
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The 72 year-old rock and blues legend, also known as Slowhand, played Heir to Blackie at headlining events in the early 1990s.
These included his 24 Nights concerts at the Royal Albert Hall, a tour of Japan with Beatle George Harrison and Bob Dylan’s 30th anniversary concert at New York’s Madison Square Gardens.
Clapton, who was a member of Cream, also used it at the supergroup’s induction into the Rock and Roll Hall of Fame in 1993, playing Sunshine of Your Life.
The rock and blues guitarist, singer, and songwriter is the only three-time inductee to the Rock and Roll Hall of Fame.
Clapton has been hailed as one of the most important and influential guitarists of all time.
In the mid-1960s he left the Yardbirds to play with John Mayall & The Bluesbreakers and later formed the power trio Cream with drummer Ginger Baker and bassist Jack Bruce.