Background:  S100A6, a calcium‐binding protein in the S100 family, has been observed in melanocytic nevi, neural tumors, fibrohistiocytic tumors and is overexpressed in melanoma. Previous studies reported S100A6 expression in atypical fibroxanthomas (AFX) but not in a small number of desmoplastic melanomas (DM). Limited data on S100A6 expression in cutaneous epithelial tumors exists in the literature. The goal of this study was to determine the specificity and sensitivity of S100A6 protein in a spectrum of cutaneous mesenchymal or epithelial tumors.Methods:  Tissue microarrays of cutaneous epithelial neoplasms, mesenchymal neoplasms, DM and malignant peripheral nerve sheath tumors (MPNST) were stained with S100A6 antibody.Results:  Eleven basal cell carcinomas (BCC) failed to express S100A6, whereas all 10 squamous cell carcinomas (SCC) expressed S100A6. Four of seven microcystic adnexal carcinomas (MAC) stained for S100A6. Tumors with duct differentiation variously expressed S100A6 protein, with two hidradenomas showing the strongest staining. Malignant spindle cell tumors, with the exception of 13 of 30 MPNST, had a high incidence of S100A6 positivity.Conclusions:  S100A6 expression may distinguish SCC from BCC, MAC from BCC and hidradenoma from other adnexal tumors. S100A6 expression favors DM over MPNST but overlap limits its diagnostic use.