We attempted to determine the reliability of surface markers in distinguishing 21 small round cell tumors from lymphoid malignancies. Using immunofluorescence on tumor cell suspensions and immunoperoxidase on fresh frozen sections, we found that specimens of neuroblastoma (n = 7), rhabdomyosarcoma (n = 7), Ewing's tumor (n = 5), and two unclassified small round cell tumors all lacked human HLA-DR antigens. Each of eight tumors tested also lacked common leukocyte antigen (T200). In each of 13 cases studied, neither polyvalent surface immunoglobulin (sIg) nor receptors for sheep erythrocytes (E), complement (EAC), or the Fc portion of IgG immunoglobulin (EA) were found. Conversely, we found HLA-DR and/or T200 antigens, usually one or more receptors for E, EAC, or EA, and not infrequently, monoclonal sIg on malignant cells in each of 42 cases of lymphocytic lymphoma and leukemia. We conclude that study of surface DR and T200 antigens, sIg, and receptors for E, EAC, and EA aids the differential diagnosis of small round cell tumors from lymphocytic lymphoma and leukemia.