Three members of a family with severe epidermolytic hyperkeratosis were successfully treated with topical tretinoin therapy. During hospitalization a controlled paired-comparison study was performed treating one half of each patient with retinoic acid and the other half with the appropriate placebo. The retinoic acid was evaluated at concentrations 0.05% and 0.1% and in both an alcohol-polyethylene glycol solution as well as in a cream base. Special studies, using the scanning electron microscope, revealed basic alterations in the ultrastructure of diseased skin which help to explain the repeated pyodermas, persistent malodor, and lack, of a physiologically effective stratum corneum with the disorder. While the ineffective barrier function permitted systemic effects from topical corticosteroid applications in one patient, no adverse reactions were seen with prolonged, full-body tretinoin therapy over a period of eight months. Significant therapeutic results were recorded photographically.