Clear cell sarcoma (CCS) is an uncommon, clinicopathologically distinct neoplasm that typically arises in association with tendons and aponeuroses. It shares several histologic and ultrastructural features with malignant melanoma. Clear cell sarcoma occasionally may be confused with other tumors of soft tissue that have a predominantly epithelioid appearance, including epithelioid leiomyosarcoma, epithelioid neurofibrosarcoma, synovial sarcoma, and epithelioid sarcoma. To assess the potential contribution of immunohistochemistry to this differential diagnosis, a panel of immunostains was applied to examples of each of these neoplasms. All six CCSs contained vimentin, and five were reactive with the melanoma-specific monoclonal antibody HMB-45. In addition, five CCSs expressed neuron-specific enolase, four cases displayed S100 protein, and four examples contained LN3 antigen. Synaptophysin and Leu-7 antigen were present in one case each. Cytokeratin, epithelial membrane antigen, carcinoembryonic antigen, desmin, muscle-specific actin, and leukocyte common antigen were invariably absent. No other primary epithelioid neoplasm of soft tissue reacted with HMB-45. Clear cell sarcoma could be separated from epithelioid leiomyosarcoma by the presence of desmin and muscle-specific actin in the latter neoplasm. Similarly, both synovial sarcoma and epithelioid sarcoma differed from CCS by their expression of cytokeratin and epithelial membrane antigen. Clear cell sarcoma and malignant melanoma were immunohistochemically indistinguishable, supporting the concept that they share a common pattern of differentiation.