The hereditary palmar-plantar keratodermas are a heterogeneous group of disorders characterized by hyperkeratosis of the palms and soles and distinguishable by other clinical characteristics, associated abnormalities, and mode of inheritance. We report a family with a new autosomal dominant condition with clinical similarities to mal de Meleda and Greither's disease. Biochemical characteristics before and during treatment with oral isotretinoin were typical of hyperproliferative epithelium with expression of the 48-kd keratin. Ultrastructural abnormalities were qualitatively reduced during treatment, but the abnormal keratohyaline aggregations were still seen. Clinical improvement with treatment was marked and directly correlated with dosage.