A variety of benign and malignant skin lesions was stained for the presence of prekeratin using an unlabeled antibody peroxidase-antiperoxidase method and an antibody raised against human prekeratin protein. No prekeratin could be detected in benign or malignant lesions derived from melanocytes, and prekeratin could not be found in atypical fibroxanthoma, Kaposi's sarcoma, angiosarcoma, dermatofibrosarcoma protruberans, and leiomyosarcoma. Paget's cells did not contain prekeratin. Varying staining intensities were observed in keratinocytic atypical hyperplasias. Of particular interest is the observation that many spindle cell lesions that were difficult to identify with 100% assurance from routine stains could be positively identified as squamous cell carcinoma after prekeratin was found in the atypical cells.