Reactivity of CD8+ T lymphocytes against human melanoma has been extensively characterized, but little is known about melanoma Ags recognized by CD4+ lymphocytes. We have identified CD4+ CTL that recognize shared melanoma Ag(s) expressed by autologous melanoma cells and a subset of allogeneic melanomas. The same Ag(s) was shared by autologous and positive allogeneic melanomas by cross-blocking experiments. Cytotoxicity was directed against epitopes presented by HLA-DR on target melanoma cells, and allelic typing revealed that cytotoxicity was restricted through HLA-DR15. These CD4+ T cells released IFN-gamma, IL-4, and TNF-alpha, but not IL-2, in response to HLA-DR15+ target cells. CD4+ T cells did not lyse DR15+ nonmelanoma cell types, including melanocytes or fibroblasts (induced to express HLA-DR by IFN-gamma). Thus, by cytotoxicity assays, shared Ags were only recognized on melanoma cells but not on normal melanocytes. In summary, this analysis shows that melanoma cells share an Ag that is presented by HLA-DR15.