We investigated the mechanism of host immune responses against two interferon-gamma (IFN-gamma) gene-transduced tumors, plasmacytoma MOPC104E(Mu gamma) and mammary cancer SC115(K gamma), which originally had weak immunogenicity. Both IFN-gamma-producing tumor cells had reduced tumorigenicity and were rejected by syngeneic mice. The rejection was completely blocked by in vivo treatment with anti-CD8 or anti-IFN-gamma monoclonal antibodies. While anti-CD4 monoclonal antibody also blocked the rejection of SC115(K gamma), it enhanced the initial tumor growth of MOPC104E(Mu gamma). Specific protection against subsequent challenge with the respective parental tumor cells was demonstrated in mice which rejected the IFN-gamma-producing tumor cells. Cultured lymphocytes derived from immunized mouse spleens had cytotoxic T cell activity against parental tumor cells, as well as against cells that produced IFN-gamma. These findings indicate that the antitumor effects are mediated by cytotoxic T cells and, partly, by helper T cells, and that locally secreted IFN-gamma plays an important role in generating these effector cells.