We present a series of 18 atypical apocrine mixed tumors of the skin characterized by architectural and/or cytologic atypia but which nevertheless do not qualify these lesions as carcinomas. There were 15 males and 3 females, and all but I presented with solitary nodules ranging in size from 4 to 20 mm; I female had a large tumor of 12 cm. The tumors were preferentially located on the head area, especially the face (13 cases). Other locations included the lower extremities (3) and inguinal area (2). In all patients, surgical excision of the tumors was performed. Clinical follow-up was available in 11 cases and ranged from I to 24 years (mean 9.6 y; median 5 y). No recurrences or metastases were documented. Overall, the lesions manifested a rather benign architecture, usually with good circumscription, lack of capsular breach or hypercellularity; however, some asymmetry, focally irregular infiltrationlike or pushing tumorous borders were seen. Microscopically, 17 cases conformed to the so-called hyaline cell-rich variant and showed multinucleated, bizarre, hyperchromatic cells in hyaline cell areas that had a myoepithelial immunophenotype; in 1 case, atypical mitotic figures were noted. One case showed mild nuclear pleomorphism in the ductal component. Tumors were negative for p53, including bizarre giant cells that did not label with Ki-67. UItrastructurally, hyaline cells exhibited features consistent with myoepithelial differentiation. Seven cases studied by immunohistochemistry proved negative for HER-2/neu (c-erbB-2) protein expression, and the HER-2/neu gene was not amplified by fluorescence in situ hybridization analysis in 5 cases tested. As controls, 4 authentic malignant mixed tumors were studied, but these likewise tested negative for HER-2/neu protein expression and showed no gene amplification; 1 malignant mixed tumor had polysomy 17. We conclude that some atypical cytoarchitectural features in apocrine mixed tumors, albeit worrisome, do not indicate a malignant change.