The Rookie (Red Sox Locker Room), a painting by Norman Rockwell, is to lead a May 22 sale of American art at Christie's with an estimate of $20m-30m.
The work shows a new Redsox recruit arriving at the team's training ground in Sarasota, Florida.
It depicts seasoned veterans Frank Sullivan, Jackie Jensen and Sammy White, all of whom travelled to Rockwell's Massachusetts studio to pose for the work.
Legendary hitter Ted Williams is also featured, but was painted from photographs.
Elizabeth Beaman, Senior Specialist of American Art at Christie's, commented: "During his lifetime, Norman Rockwell was witness to such important artistic movements as Impressionism, Cubism, Surrealism, and Abstract Expressionism.
"In choosing a path of illustration, however, he became as ubiquitous to the American public as the images he created.
"With over 800 magazine covers to his name, Rockwell earned the reputation of America's preeminent illustrator and helped forge a sense of national identity through his art.
"The renewed demand for these uniquely American works of art is evidenced by their increasingly strong prices in recent seasons and this particular painting, capturing America's favorite pastime, will surely have wide ranging appeal among collectors."
Last year Rockwell's Saying Grace broke the artist's auction record when it sold for $46m at Sotheby's New York, more than doubling its $20m estimate.
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