Distinguishing low grade endometrial stromal sarcoma (ESS) from benign smooth muscle proliferations like cellular leiomyoma (CL) can be problematic; because of differing treatments and prognosis, this distinction is important. The authors tested the hypothesis that low grade ESS could be distinguished from CL by immunohistochemistry using a panel of antibodies that have not previously been used in this setting. Antibodies to calponin, smooth muscle myosin heavy chain (SMM-HC), the Wilms tumor gene product (WT-1), and CD10 were applied to 14 cases of ESS (10 low grade, 4 high grade) and 9 CL. Among low grade ESS, 3 of 10, 3 of 10, 9 of 10, and 10 of 10 were positive for expression of calponin, SMM-HC, WT-1, and CD10, respectively. Of CL, all 9 were positive for calponin, SMM-HC, and WT-1, whereas 3 of 9 marked with antibodies to CD10. Overall, SMM-HC and calponin were expressed strongly in CL but weakly expressed in ESS; the converse was true for CD10. Expression of WT-1 and the reticulin-staining pattern do not discriminate between these two tumors. Antibodies to SMM-HC, CD10, and calponin can reliably distinguish ESS from CL.