Infection of adult BALB/c mice with Friend disease virus resulted in marked suppression of the ability of the animals to respond to a potential immunizing inoculum of sheep erythrocytes as detected both on the cellular and humoral antibody level. Whereas normal noninfected animals had a vigorous immune response to erythrocytes, with the appearance of relatively large numbers of antibody plaque-forming cells in their spleens, infected mice generally had a markedly depressed response. The timing of virus infection in relation to immunization was an important factor since the greatest immunosuppression occurred in mice infected 3, 8 or 21 days before immunization. Less suppression occurred in mice infected the same day as immunization. The peak response was depressed in all mice, regardless of the day of antigen injection, when the number of PFC was calculated per million leukocytes rather than per whole spleen. Appearance of 7 S IgG PFC late in the immune response was markedly inhibited in all infected mice, even those receiving FDV after immunization. The “background” counts of 19 S PFC preexisting in spleens of both nonstimulated control and FDV-infected mice were similar. Serum hemagglutinin and hemolysin titers were only slightly, if at all, suppressed in mice infected the same day as immunization or 2 days later. The peak serum titer was markedly suppressed in animals infected 3 or 8 days prior to immunization. The amount of 2-mercaptoethanol (2ME) resistant 7 S antibody in serum specimens of infected mice was less than in control mice. Immunosuppression appeared to be related to leukocytosis and splenomegaly. However, immunosuppression was usually detectable prior to overt splenomegaly in mice infected simultaneously or after immunization. Although the mechanisms involved in FDV induced immunosuppression are unknown, the effects of leukemogenic viruses such as FDV on antibody-forming cells per se, on progenator or stem cells, and/or antigen-processing cells, such as macrophages, were discussed in relation to both immunogenesis and virus tumorigenesis.