Recent studies of Class II histocompatibility antigen expression in bone and soft tissue sarcomas have suggested that malignant fibrous histiocytoma (MFH) may express HLA-DR, whereas histologically similar pleomorphic, epithelioid, and spindle cell malignant neoplasms generally do not. To test whether these observations are reproducible in the differential diagnosis of soft tissue sarcomas, anti-HLA-DR antibodies LK8D3 and LN3 were applied to formalin-fixed, paraffin-embedded sections of MFH, neurofibrosarcoma (NFS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), angiosarcoma (AS), Kaposi's sarcoma (KS), chondrosarcoma (ChS), "dedifferentiated" chondrosarcoma (DChS), osteosarcoma (OS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS; malignant melanoma of soft parts). The only consistent difference in Class II antigen expression was seen in the group of neoplasms composed of large polygonal cells. Among the latter lesions, four of six clear cell sarcomas were labeled by LK8D3 or LN3, but none of 12 epithelioid sarcomas were reactive. Otherwise, a diversity of tumors in other morphologic categories expressed Class II antigens, with no clear diagnostic patterns. These results may be of use in the diagnostic separation of large cell epithelioid tumors of soft tissue, but neither LN3 nor LK8D3 appears to be helpful in the identification of other sarcomas.