The in vitro cytotoxic response to human melanoma is characterized by CD3+ CD8+ T-cells which recognize shared peptide antigens presented in the context of HLA class-I-encoded gene products. We report here studies of a CD3+, CD4+, CD8-, HLA-A2-restricted, melanoma-specific cytotoxic T-cell clone derived by limiting dilution from a T-cell line induced in PBLs from a melanoma patient following in vitro stimulation with an HLA-A2-matched melanoma cell line. The CD4+ cytotoxic T-cell clone is lytic only for melanomas which share the HLA-A2 allele, and the cytotoxicity is blocked by antibody to the T-cell receptor and by antibody to HLA class I. The clone proliferates only following stimulation with HLA-A2-matched melanoma tumor cells. The data suggest that cytotoxic CD4+ T-cells may play a significant role in immunity to melanoma, and HLA class-I-restricted recognition of melanoma may not necessarily require the CD8 molecule on the lytic T-cell.