Background. The elucidation of CD4+ T helper (Th) cell traits is important for the understanding of immunoregulatory mechanisms in patients with cancer, in particular the Th-cell effect on cytotoxic CD8+ tumor-specific lymphocytes (CTL). Methods. Sixty-six T-cell receptor αβ+/CD4+ clones were generated from tumor-infiltrating lymphocytes of five patients with melanoma and classified into subsets by cytokine production. Transwell experiments were performed to test how the soluble factors of each Th-clone subset affected the cytotoxicity of the tumor-specific CTL against autologous tumor. Results. Th0 clones enhanced cytotoxicity of the CD8+ CTL compared with control CTL cultured in cytokine-free medium. Th1-clone supernatant also enhanced cytotoxicity by CD8+ CTL. In contrast, Th2 clones decreased killing compared with control CTL. Replacement of the Th clones by exogenous interleukin (IL)-2 in concentrations similar to that produced by Th0 and Th1 clones enhanced cytotoxicity. However, suppression of cytotoxicity was observed when similar concentrations of IL-4 were added instead. The helper effect of Th0-soluble factors could be inhibited by anti-IL-2 antibody, whereas anti-IL-4 antibody did not show a significant enhancement. Conclusions. The majority of the CD4+ tumor-infiltrating lymphocytes (Th0) in patients with melanoma enhance the CTL response to autologous tumor by their soluble factors, whereas Th2 cells suppress the CTL response.