Although ‘aberrant’ expression of the epithelial markers, cytokeratin (CK) and epithelial membrane antigen (EMA), in leiomyosarcoma has been described previously, there has not been a study of this phenomenon with clinicopathological correlation in a large series of lesions at different anatomical sites. We investigated systematically the immunohistochemical reactivity for CK and EMA in 100 cases of leiomyosarcoma. CK and EMA were positive in 38% and 44% of the cases, respectively. Although staining was usually focal, extensive immunoreactivity was observed in 11% with CK and 6% with EMA. There was no correlation between immunoreactivity for CK and EMA in leiomyosarcomas and non-neoplastic smooth muscle at the same location. Immunoreactivity for CK and EMA was not correlated with the location, age, sex, histological grade, or histological features, except for more frequent EMA positivity in vascular and uterine tumors than in soft tissue cases. These results indicate that CK and/or EMA-positive leiomyosarcomas do not have distinctive clinicopathological features differing from those of negative cases. However, the considerable frequency of immunoreactivity for these epithelial markers in leiomyosarcoma, occasionally with diffuse and strong immunopositivity, should be recognized as a potentially serious diagnostic pitfall in the differential diagnosis of other malignant spindle cell neoplasms.