Epidermolytic hyperkeratosis (EHK) is a rare autosomal dominant disorder of cornification. While different clinical presentations of EHK have been described, the distinctions have not been clear. We have examined 52 patients with EHK from 21 families in an effort to define and characterize the specific clinical features of this disorder.We found that several features were useful for separating patients with EHK into clinical groups. The most distinctive characteristic was presence vs absence of severe palmoplantar hyperkeratosis. Twenty-nine patients in six families had this finding and were grouped into "PS types" (those with severe palm/sole hyperkeratosis). The remaining 23 patients (from 15 families) were classified as "NPS types" (those without severe palm/sole hyperkeratosis). We identified three distinct PS types and three distinct NPS types. The classification was always found to be consistent in all affected family members. In those families in which mutations were defined, keratin 1 mutations were identified in the PS types and keratin 10 mutations in the NPS types.We were able to classify our cohort of 52 patients with EHK from 21 families into distinct types. There was a correlation between presence or absence of severe palm/sole hyperkeratosis and the specific keratin involved.