The mink cell focus-inducing (MCF)-247 virus, originally isolated from an AKR thymoma, is lymphomagenic in AKR mice but not in the ecotropic virus-negative NFS mouse strain. Analysis of sensitivity to lymphoma-induction by AKR-247 MCF virus in genetic hybrids between these two strains showed that F1 mice inoculated as sucklings were uniformly sensitive, whereas those inoculated as weanlings were generally resistant. In NFS backcross mice inoculated as sucklings, inheritance and expression of endogenous ecotropic virus from AKR was an essential correlate of replication of MCF virus and subsequent development of lymphoma. However, one-third of the mice expressing ecotropic virus and replicating the inoculated MCF virus did not develop lymphoma. The results suggested that an additional gene that influenced development of lymphoma may be involved, and that mice inheriting both virus-inducing loci from AKR were more susceptible than those inheriting only one. These findings indicate that the causal role of ecotropic virus infection in spontaneous thymomagenesis in AKR mice involves not only the generation of leukemogenic MCF viruses but also the establishment of permissiveness for their growth.