An IgM human monoclonal antibody (human MAb) was generated by fusing lymph node cells Isolated from a surgical specimen of malignant melanoma with the heteromyeloma cell line SHMD-33. The antibody, designated 7c11.e8, reacted with surface antigens on human melanoma cells as shown by live cell immunofluorescence and absorption assays. The MAb 7c11.e8 reacted with DSI, SPG, GM4, GM3 and GD3 In enzyme-linked Immunosorbent assays (ELISA), and did not react with GD2, GM1, GM2, GD1a, GD1b, GT1b and a number of neutral glycosphingollplds. The main binding epitope for the MAb was, therefore, the terminal N-acetylneuramlnlc acid 2–3 Gal linked by a β1–1 bond to the ceramlde, or a β-4 bond to glucose or glucosamine. As shown by immunohlstochemlcal assays, 7c11.e8 antigen was expressed on all melanoma tumour tissues, and on a few samples of colon carcinoma, normal colon, skin, spinal cord, kidney and liver. However, other normal organs such as breast, lung, small Intestine, stomach and lymph nodes did not react with the MAb. In the presence of human serum the antibody Initiated a strong lysis of melanoma tumour cells In complement-dependent cellular cytotoxicity (CDCC) assays. This study demonstrates that It Is possible to Isolate human monoclonal antibodies directed to cell surface antigens using viable cell assays In the screening protocol. The preferential binding of 7c11.e8 to melanoma tissues and the reactivity with two of the major melanoma gangliosides (GM3 and GD3) suggest that 7c11.e8 may provide a useful reagent for diagnosis and therapy of malignant melanoma.