Proceeds from the Wednesday sale are to benefit a drug and alcohol treatment center Clapton founded in the West Indies.
The British artist has donated 70 guitars and 70 amps to the Bonhams New York sale.
The replica Fender Stratocaster "Blackie" guitar is inscribed in silver felt pen "Eric Clapton 2010." The original "Blackie" sold at Christie's in 2004 for $959,500. Bonhams says it's the most expensive guitar ever sold at auction.
The 65-year-old Rock and Roll Hall of Famer is a recovered addict who established the nonprofit Crossroads Centre in Antigua in 1998.