Summary Syngeneic X-irradiated Friend, Moloney, and Rauscher (FMR) lymphomas readily induce transplantation resistance in C57BL/6 mice. Similar resistance is more difficult to induce in BALB/c mice. To determine whether this difference in response is due to a lesser immunogenicity of FMR cells of BALB/c origin, C57BL/6 mice were pretreated with viable or X-irradiated BALB/c FMR cells, or with X-irradiated C57BL/6 FMR cells, and were challenged with FMR lymphomas of C57BL/6 origin. The reverse experiments were performed in BALB/c recipients. All FMR lymphomas of both strains induced strong transplantation resistance in C57BL/6 mice. Therefore, FMR lymphomas of BALB/c origin were immunogenic in C57BL/6 mice. However, FMR cells of either strain generally induced only weak or nondetectable resistance in BALB/c mice. X-irradiated FMR lymphomas of both strains released varying amounts of infectious virus when inoculated into BALB/c newborns. Lymphomas releasing lesser amounts of virus were usually the more effective immunogens for the induction of transplantation resistance in BALB/c mice. It was therefore postulated that BALB/c mice were less able than C57BL/6 mice to handle immunologically large quantities of virus. This was substantiated by the markedly greater susceptibility of weanling BALB/c mice than C57BL/6 mice to Rauscher virus, as judged by the induction of splenic enlargement, viremia and death. It is suggested that the inoculation of highly susceptible BALB/c mice with lymphomas that release large quantities of virus may impede or obscure specifically or nonspecifically the immunologic reactivity to a subsequent tumor challenge.