Clapton's choice of electric guitars has been as notable as the man himself, and alongside Hank Marvin, The Beatles and Jimi Hendrix, Clapton exerted a crucial and widespread influence in popularizing particular models of the electric guitar. With the Yardbirds, Clapton played a Fender Telecaster, a Fender Jazzmaster, a double-cutaway Gretsch 6120 and a 1964 Cherry-Red Gibson ES-335. He became exclusively a Gibson player for a period beginning in mid-1965, when he purchased a used Gibson Les Paul Sunburst Standard guitar from a local guitar store in London. Clapton commented on the slim profile of the neck, which would indicate it as a 1960 model.

1967 he acquired his most famous guitar in this period, a 1964 Gibson SG. Just before Cream's first U.S. appearance in 1967, Clapton's SG, Bruce's Fender VI, and Baker's drum head were all repainted in psychedelic designs created by the visual art collective known as The Fool. In 1968 Clapton bought a Gibson Firebird and started using the 1964 Cherry-Red Gibson ES-335 again. The aforementioned 1964 ES-335 had a storied career. Clapton used it at the last Cream show in November 1968 as well as with Blind Faith, played sparingly for slide pieces in the 1970s, heard on "Hard Times" from Journeyman, the Hyde Park live concert of 1996 and the From the Cradle sessions and tour of 1994/95. It was sold for $847,500 at the 2004 auction. Gibson produced a limited run of 250 "Crossroads 335" replicas. The 335 was only the second electric guitar Clapton bought.

In July 1968, Clapton gave George Harrison a red, refinished Les Paul. In the following September, Clapton played the guitar on the Beatles' studio recording of "While My Guitar Gently Weeps". His SG found its way into the hands of George Harrison's friend Jackie Lomax, who subsequently sold it to musician Todd Rundgren for US$500 in 1972. Rundgren restored the guitar and nicknamed it "Sunny", after "Sunshine of Your Love". He retained it until 2000, when he sold it at an auction for US$150,000. At the 1969 Blind Faith concert in Hyde Park, London Clapton played a Fender Custom Telecaster, which was fitted with Brownie's neck.

In late 1969, Clapton made the switch to the Fender Stratocaster. "I had a lot of influences when I took up the Strat. First there was Buddy Holly, and Buddy Guy. Hank Marvin was the first well known person over here in England who was using one, but that wasn't really my kind of music. Steve Winwood had so much credibility, and when he started playing one, I thought, oh, if he can do it, I can do it." First was "Brownie" used during the recording of Eric Clapton which in 1974 became the backup to the most famous of all Clapton's guitars, "Blackie". In November 1970 Eric bought six Fender Stratocasters from the Sho-bud guitar shop in Nashville, Tennessee while on tour with the Dominos. He gave one each to George Harrison, Steve Winwood and Pete Townshend.

Clapton assembled the best components of the remaining three to create "Blackie", which was his favourite stage guitar until its retirement in 1985. It was first played live 13 January 1973 at the Rainbow Concert. Clapton called the 1956/57 Strat a "mongrel". On 24 June 2004, Clapton sold "Blackie" at Christie's Auction House, New York for $959,500 to raise funds for his Crossroads Centre for drug and alcohol addictions. "Brownie" is now on display at the Experience Music Project. The Fender Custom Shop has since produced a limited run of 275 'Blackie' replicas, correct in every detail right down to the 'Duck Brothers' flight case, and artificially aged using Fender's 'Relic' process to simulate years of hard wear. One was presented to Eric upon the model's release and used for three numbers during a concert at the Royal Albert Hall in May 17, 2006.

In 1971, Clapton gave a signed guitar to the Hard Rock Cafe to designate his favourite bar stool. Pete Townshend also donated one of his own guitars, with a note attached: "Mine's as good as his! Love, Pete."

In 1988, Fender honored Clapton with the introduction of his signature Eric Clapton Stratocaster. These were the first two artist models in the Stratocaster range and since then, the artist series has grown to include models inspired both by Clapton's contemporaries such as Rory Gallagher, Mark Knopfler, Jeff Beck, Stevie Ray Vaughan, and by those who have influenced him such as Buddy Guy. Clapton uses Ernie Ball Slinky and Super Slinky strings. Clapton has also been honoured with signature-model 000-28EC and 000-42EC acoustic guitars made by the famous American firm of C.F. Martin & Company/ His 1939 000-42 Martin that he played on the Unplugged album sold for $791,500 at auction.[49] Clapton plays a custom 000-ECHF Martin these days.

In 1999, Clapton auctioned off some of his guitar collection to raise more than $5 million for continuing support of the Crossroads Centre in Antigua, which he founded in 1997. The Crossroads Centre is a treatment base for addictive disorders such as drugs and alcohol. In 2004, Clapton organized and participated in the Crossroads Guitar Festival to benefit the Centre. A second guitar auction, including the "Cream" of Clapton's collection – as well as guitars donated by famous friends – was also held on 24 June 2004. His Lowden acoustic guitar sold for $41,825. The total revenue garnered by this auction at Christie's was US $7,438,624.

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Eric Patrick Clapton, CBE (born 30 March 1945) is an English blues-rock guitarist, singer, songwriter and composer. Clapton has been inducted into the Rock and Roll Hall of Fame as a solo performer, as well as a member of rock bands the Yardbirds and Cream. He is the only person ever to be inducted three times.

Often viewed by critics and fans alike as one of the most important and influential guitarists of all time, Clapton was ranked fourth in Rolling Stone magazine's list of the "100 Greatest Guitarists of All Time" and #53 on their list of the Immortals: 100 Greatest Artists of All Time.

Although Clapton has varied his musical style throughout his career, it has always remained grounded in the blues; despite this focus, he is credited as an innovator in a wide variety of genres. These include blues-rock (with John Mayall & the Bluesbreakers and The Yardbirds) and psychedelic rock (with Cream). Clapton's chart success was not limited to the blues, with chart-toppers in Delta Blues (Me and Mr. Johnson), Adult contemporary ("Tears in Heaven") and reggae (Bob Marley's "I Shot the Sheriff"; he is often credited for bringing reggae and Bob Marley to the mainstream). Two of his most successful recordings were the hit love song "Layla", which he played with the band Derek and the Dominos, and Robert Johnson's "Crossroads", which has been his staple song since his days with Cream.