Homeobox (HOX) genes share a highly conserved 183-bp sequence. The encoded proteins are capable of binding to specific DNA sequences and functioning as transcription factors. HOX genes play a critical role in the temporal and spatial differentiation of cells during embryogenesis. In several adult tissues, HOX genes are expressed in a constant, tissue-specific pattern, whereas in malignant tumors of these tissues an altered expression pattern was found. We investigated the expression of HOXC4 in adult normal skin by reverse-transcription polymerase chain reaction and non-radioactive RNA in situ hybridization. Moreover, HOXC4 expression was studied in various epidermal neoplasms (solar keratosis, six specimens; Bowen's disease, four; squamous cell carcinoma, nine; basal cell carcinoma, three) by RNA in situ hybridization. HOXC4 was found to be expressed in the suprabasal layers of the epidermis in normal skin specimens and the adjacent non-lesional epidermis of all other specimens. Atypical keratinocytes of solar keratoses and Bowen's disease as well as basaloid cells of basal cell carcinomas were negative. In squamous cell carcinoma, well differentiated areas with keratinization showed HOXC4 expression, whereas poorly differentiated areas were negative. Immunostaining with an antibody against cytokeratin 10, a marker of epidermal differentiation, was performed. A good correlation between the distribution pattern of HOXC4 and cytokeratin 10 in the lesions examined was found. These results suggest that HOXC4 is expressed mainly in differentiated keratinocytes. Lack of differentiation (as in neoplastic cells) is accompanied by downregulation of HOXC4 expression.