A 56-year-old white woman developed a distinctive skin eruption over her mammary, lumbosacral, and pubic areas 2 weeks after the start of esomeprazole therapy for dyspeptic symptoms. Skin biopsy disclosed a spongiotic dermatitis with predominantly lymphocytic dermal infiltrate. Treatment with a tapering dose of corticosteroid and withdrawal of the suspected drug led to a rapid resolution of the eruption without residual dyschromia. Patch testing with esomeprazole 2% in petrolatum was negative at 48 and 72 hours but became positive on day 6. Oral-controlled provocation test induced the reappearance of the lesions over the mammary areas, confirming the putative involvement of this drug. Therefore, the patient was diagnosed as having a nonpigmented fixed drug eruption associated with esomeprazole. This compound is a proton-pump inhibitor developed as the S-isomer of omeprazole to improve its pharmacokinetic properties. Reports of cutaneous reactions to proton-pump inhibitors are quite common, but reports of such reactions to esomeprazole are rare, which demonstrates the need for higher clinical awareness and knowledge of reactions to these drugs.