GM2, GD2, and GD3 gangliosides are expressed on the surface of human melanoma cells and represent potential targets for immunological control of melanoma growth by monoclonal antibodies and active immunization. The immunogenicity of GM2 was investigated by analyzing the humoral immune response of melanoma patients to vaccination with cell lines selected for high GM2 expression and with vaccines containing purified GM2. The whole-cell vaccine and vaccines containing purified GM2 and bacillus Calmette-Guérin (BCG) elicited GM2 antibody in a high proportion of patients, particularly in GM2/BCG-vaccinated patients pretreated with cyclophosphamide and given a GM2/BCG booster immunization. Vaccines containing purified GM2 and Salmonella minnesota R595 as the adjuvant were also effective, but only in patients pretreated with cyclophosphamide. GM2 antibodies in vaccinated patients were of the IgM class and were cytotoxic for GM2-positive targets in the presence of human complement.