Rejection of the Moloney virus-induced YAC lymphoma of strain A origin by semisynegeneic F1 hybrids has previously been shown to correlate with the levels of natural killer (NK) cell activity in the same F1 hybrids against this target cell line in vitro. In the present study, YAC and another Moloney virus-induced lymphoma,, YWA, derived from the A congenic A.SW strain, were tested for F1 hybrid resistance after s.c. inoculation of small numbers of cells into syngeneic and semisyngeneic F1 mice. While YAC cells invariably grew progressively once they formed a palpable tumor, regression of YWA tumors was frequently observed in both susceptible and resistant genotypes. The hybrid resistance pattern for YAC and YWA differed in one important respect: outcross of the syngeneic host to the A-congenic A.BY strain introduced a strong H-2b-associated resistance factor against YWA, but not against YAC. Compared to YAC, which is highly NK-sensitive and rapidly eliminated from mice with high NK activity, YWA was insensitive to NK-mediated lysis in vitro and [125I] UdR-labelled YWA cells were not eliminated more efficiently from the highly resistant (A.SW X A.BY) F1 then from the parental strain in short-term (4-18h) in vivo rejection assays. It was therefore concluded that the H-2b-associated resistance against YWA was independent of NK cells or other rapidly acting effector mechanisms. Moreover, thymectomy, followed by irradiation and fetal liver reconstitution, completely abolished the resistance against YWA but left the resistance against YAC virtually intact. These data suggest that two lymphomas induced by the same agent can be rejected by different effectors. The NK-resistant YWA lymphoma is rejected by a T-dependent mechanism, while the resistance against the inoculation of the highly NK-sensitive YAC line is T-independent and, in all probability, mediated by NK cells.