The histologic differential diagnosis of skin lesions characterized by large, atypical, clear cells in the epidermis includes Bowen's disease, Paget's disease (mammary and extramammary), malignant melanoma in situ (pagetoid precancerous melanosis), mycosis fungoides, Spitz nevus, and artifact. Our experience with these lesions indicates that these diseases can be differentiated immunohistologically by the standard peroxidase-antiperoxidase technique, using antibodies directed against keratin (KER), carcinoembryonic antigen (CEA), and S-100 protein (S-100). Based on a study of 11 cases of Bowen's disease, eight cases of Paget's disease, and nine cases of malignant melanoma in situ, we conclude that the atypical clear cells of Bowen's disease stain only with antibodies to KER; those of Paget's disease, exclusively with antibodies to CEA; and those of malignant melanoma in situ, with antibodies to S-100. Additionally, we report a case in which clinical and histologic findings suggested Bowen's disease, but immunohistologic findings supported the diagnosis of Paget's disease.