Epithelial-myoepithelial carcinoma (EMC) of the salivary glands is an uncommon, low-grade malignant tumor. A recent report demonstrates sebaceous differentiation in this tumor even though its significance has never been documented as a precise histologic variant. Six cases of EMC exhibiting sebaceous differentiation (sebaceous EMC) of the parotid gland were analyzed for their clinicopathologic features and immunohistochemical characteristics. In addition, primary salivary sebaceous carcinomas were also examined for comparison. In our series, the incidence of sebaceous EMC was 0.2% among 3012 cases of parotid gland tumors and 14.3% of all EMC cases. The 6 patients comprised 2 men and 4 women, age ranging from 77 to 93 years (mean, 83.7 y). Neither cervical lymph node nor distant organ metastases were found in any cases of sebaceous EMC and no patients died of disease, though local recurrences developed in 1 patient. Conversely, cervical lymph node metastasis was detected in 2 of 3 patients with sebaceous carcinoma, 1 of whom died of disease at 12 months. Histologically, all 6 tumors had an area of sebaceous differentiation admixed with features of bilayered ductal structures typical of EMC. A component of sebaceous differentiation was distributed diffusely in 4 tumors and focally in 2. Cytologic atypia of sebaceous EMCs was lesser than that of sebaceous carcinomas. Immunohistochemically, putative myoepithelial markers such as alpha-smooth muscle actin, calponin, p63, cytokeratin 14, S-100 protein, and vimentin were highly expressed in sebaceous EMC. However, the expression of the latter 4 markers was also observed in primary sebaceous carcinomas, whereas these tumors were all negative for alpha-smooth muscle actin and calponin. Positive immunoreactivity for epithelial membrane antigen, adipophilin, and perilipin confirmed sebaceous differentiation in EMC. These results indicate that sebaceous EMC is a low-grade malignancy, similar to conventional EMC. Our data also suggest that immunohistochemical examination of specific myoepithelial markers is helpful in distinguishing sebaceous EMC from sebaceous carcinoma, which may occasionally be associated with an aggressive clinical course.