Keratolysis exfoliativa (KE) is a palmoplantar eruption of air-filled bullae on an erythematous base, which results in lamellar peeling with hallmark superficial collarettes of scale. It is distinct from other diseases of volar skin, such as dyshidrosis, contact dermatitis, tinea, epidermolysis bullosa, and acral skin peeling. We present a 55-year-old woman with extensive disease on the hands and feet, who failed to respond to standard topical therapy but showed a marked dose-response improvement with the use of oral acitretin. Recent histopathologic and molecular studies have linked KE to premature corneo-desmosomal disruption. Acitretin has previously been used to treat diseases of abnormal corneocyte desquamation, for example Netherton's disease. To the best of our knowledge, this report is the first that documents the efficacy of the use of systemic acitretin in KE.