A 41‐year‐old man being treated for severe esophageal reflux disease developed red, exfoliative scaling on his back, trunk, and legs after taking omeprazole 20 mg twice/day for 3 months. He also had redness and extreme sloughing of the skin on his hands. Even after he discontinued omeprazole and after several courses of topical and systemic steroids, symptoms continued to occur 18 months after treatment, mostly localized to the hands. Exfoliative dermatitis is associated with many drugs, but omeprazole has been implicated only once before in the literature.