Original artwork for the cover of Action Comics #309 by Curt Swan is leading an online auction at Hake's Americana and Collectibles with a bid of $19,965.
The issue in the sale features a storyline in which JFK disguises himself as Clark Kent in order to help Superman conceal his true identity.
It went on sale just one week after Kennedy was assassinated on November 22, 1963.
DC was unable to recall the publication, as the distribution process had already been set in motion.
We have a selection of JFK memorabilia available to purchase.
Action Comics is credited with the invention of the superhero genre, introducing Superman in 1938.
An original Action Comics issue #1, featuring the first appearance of Superman, sold for $2.1m in 2011 - making it the most valuable comic book ever sold.
A Henry Clay Delaware Coattail flag dating to 1844 is another highlight of the sale.
Created to promote his third and final presidential campaign, the flag features a portrait of Clay in the top left corner surrounded by 26 stars.
It also features the names of his vice presidential candidate and two candidates for the senate.
Another Clay campaign flag sold for $45,350 at Heritage Auctions in June of this year, achieving a 229% increase on a $15,000 high estimate.
Another piece of comic book history, in the form of a full page of original artwork by Carl Barks for Uncle Scrooge #61, is at $11,789.
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