Friend murine leukemia virus complex (FV)-induced immunosuppression was studied by assaying splenic anti-SRBC PFC responses and plasma antibody titers in mice at various times after FV inoculation. Genes located within the H-2 complex were found to influence resistance to FV-induced immunosuppression. Near normal responses were observed in mice having the H-2a/b or H-2b/b genotype, whereas mice having the H-2a/a genotype were suppressed. This H-2 effect was observed not only in mice having heterozygous C57BL/10 X A background genes, including Rfv-3r/s, but also was apparent in mice having homozygous A-strain background genes, including Rfv-3s/s. Therefore, the Rfv-3 gene did not appear to convey resistance to FV-induced immunosuppression. The suppression in susceptible H-2a/a mice was characterized by a partial suppression of the IgM response and a profound suppression of both the primary and secondary IgG responses. Neither splenomegaly nor viremia alone appeared to be sufficient for the induction or maintenance of the immunosuppression. The mechanism of suppression was unclear, but both B lymphocyte and T lymphocyte functions appeared to be altered.