Like many of Clowes' extended works, Like a Velvet Glove Cast in Iron originally appeared in serial form in his comic book Eightball (issues #1–#10, 1989–1993) but has been reprinted as a trade paperback.

Like a Velvet Glove Cast in Iron is about a man named Clay Loudermilk and his attempts to locate his estranged wife.

For reasons unknown, Clay is in the audience at a porno theatre when he sees a bizarre BDSM feature (also titled Like a Velvet Glove Cast in Iron), the star of which is revealed to be his wife, who appears in the credits as "Madame Van Damme".

Clay is victimized by two crazed policemen, meets a religious cult led by a mass-murderer who intend to overthrow the American government, conspiracy theorists who believe that the reins of the world's political power somehow revolve around a series of dime store novelty figures, a malformed, half-fish young woman and her nymphomaniacal mother, and various other freaks and weirdos.

The happy-face icon of "Mr. Jones" also appears in various places through the story (reminiscent of Alfred E. Neuman, the mascot of Mad magazine, whose image dates at least back into the 1800s).

Images of Mr. Jones are tattooed into people, carved on to Clay's foot, as a ghost-like character, in Hitler's birthmark, and on the sign for Value Ape shops.

In issue #11 of Eightball, published after the conclusion of the Velvet Glove storyline, Clowes did a story about a hypothetical movie based on his book.