We have attempted to generate in vitro lymphocytes cytotoxic to a widely studied model of ovarian cancer in C3HeB/FeJ mice. These attempts were unsuccessful with either syngeneic or allogeneic spleen cells. The following experimental results demonstrated that this murine ovarian tumor lacks histocompatibility antigens. (a) Tumor cells were not lysed by allogeneic lymphocytes presensitized to H-2k spleen cells. (b) Tumor cells did not specifically inhibit the cell-mediated lysis of H-2k spleen cells by presensitized allogeneic lymphocytes. (c) Histoincompatible (H-2b or H-2d) and syngeneic (H-2k) mice all died with identical tumor growth patterns within 25, 30, or 35 days following the i.p. inoculation of 10(6), 10(5), or 10(4) tumor cells, respectively. (d) Tumor cells were not lysed by an anti-H-2k antiserum and complement. (e) Absorption of the anti-H-2k antiserum with tumor cells did not decrease the cytotoxicity of the antiserum. (f) Competitive inhibition of a radioimmunoassay and polyacrylamide gel electrophoresis of immunoprecipitate of radiolabeled tumor extracts failed to demonstrate an H-2 heavy chain, although a normal amount of beta-microglobulin was present. This lack of histocompatibility antigens may explain the failure to generate lymphocytes cytotoxic to this tumor. Thus, this murine ovarian tumor, which has a serologically detectable tumor-associated antigen and can be cured by nonspecific immunotherapy, may provide an excellent model for the study of successful immunotherapy in the absence of histocompatibility antigens and associated cell-mediated reactions.