Lymphoid cell subpopulations from normal donors and patients with malignant melanoma were assessed for cytotoxicity. Unfractionated mononuclear cells and T-cells from melanoma patients gave cell-mediated cytotoxic (CMC) responses to melanoma target cells but not to human fibroblasts. These specific CMC responses to melanoma cells were partially inhibited by autologous serum. Non-T-cells and nonrosetting cells from melanoma patients were not directly cytolytic for melanoma target cells; however these same subpopulations were cytotoxic in the presence of autologous serum, which indicated antibody-dependent cell cytotoxic responses. Non-T-cell subpopulations from normal donors were not cytotoxic when incubated with autologous serum. A third cytotoxic mechanism was demonstrated with complement (C3) receptor-activated lymphocytes. From both melanoma patients and normal donors, cells forming rosettes with erythrocyte-antibody-complement were nonspecifically cytotoxic for lung fibroblasts and melanoma target cells, These responses were independent of antibody, since melanoma serum presumably containing antibody to melanoma target cells neither enhanced nor blocked cytotoxicity mediated by C3 receptor-bearing lymphocytes. The results indicated that lymphoid cell subpopulations from the same melanoma patient could express at least three different lymphocyte-mediated cytotoxicity mechanisms against melanoma target cells.