A Moloney virus-induced T cell lymphoma, YAC-1, derived from A/Sn (H-2a) inbred mouse origin, was tested for hybrid resistance (HyR) after subcutaneous (s.c.) or intracerebral (i.c.) tumor cell inoculation into syngeneic and semi-syngeneic mice. The F1 hybrids (H-2a/b) between A/Sn and C57BL/6 mice more strongly resisted the s.c. inoculation of 10(6) and 5 x 10(5) cells than did syngeneic recipients. In contrast, no HyR to the i.c. inoculation of 10(4) and 10(3) cells was seen in the F1 hybrid mice. Natural killer (NK) cell activity was much higher in F1 hybrids than in syngeneic mice. 125I-iododeoxyuridine-labeled YAC-1 cells were more efficiently eliminated from the highly resistant F1 hybrids than from the parental strain in both 4 and 18 hour in vivo rejection assays via intravenous (i.v.) and s.c. injection, respectively. The remaining radioactivity of the brain, however, did not differ between these mice. Thus, there was a correlation between the in vivo resistance of F1 hybrid mice to challenge s.c. inoculation of parental tumors and their expression of lymphocyte-mediated natural cytotoxicity in vitro against those tumors. T cell depletion by thymectomy followed by irradiation and fetal liver reconstitution did not abrogate the s.c. HyR against YAC-1, whereas NK cell depletion by i.v. administration of anti-asialo-GM1 antibodies resulted in the disappearance of the resistance. Furthermore, genotypic study segregating (A/Sn x C57BL/6) F1 x A/Sn backcross mice indicated that the s.c. HyR might be attributable primarily to heterozygosity within the H-2 complex.(ABSTRACT TRUNCATED AT 250 WORDS)