Cutaneous adenoid squamous carcinoma (ASCC) is a distinctive neoplasm featuring tumor cell acantholysis. Because this lesion occasionally may prove troublesome diagnostically, we studied the clinical, histologic, and immunohistochemical features of 55 examples in order to further elucidate its characteristics. ASCC most often occurred in the skin of the head and neck in elderly patients. Of 49 patients in this series, 46 were men and 3 were women; their ages at diagnosis ranged from 25 to 90 yr, with a mean of 71. Six individuals had 2 metachronous neoplasms. ASCC generally behaved in an indolent manner, although 19% of cases did metastasize widely and prove fatal. Tumor size of greater than 1.5 cm appeared to correlate with the risk of an adverse clinical outcome. In addition, 10 patients with ASCC of the skin subsequently developed visceral malignancies. The cutaneous neoplasms were typified by invasive, tubular or pseudoglandular profiles of polygonal cells in the dermis, with glassy eosinophilic cytoplasm and focal squamous pearl formation. Connections to the overlying epidermis were commonly apparent. Immunohistochemically, ASCC demonstrated uniform reactivity for cytokeratin, but lacked markers of specialized glandular cells. These findings militate against the interpretation that such tumors demonstrate partial adnexal differentiation, and show that immunohistology may prove helpful in the differential diagnosis between ASCC and primary or metastatic adenocarcinomas of the skin.