Normal peritoneal macrophages can reverse, to a certain degree, the immunodeficiency caused by Friend leukemia viruses in mice. In vitro studies have shown, however, that spleen macrophages do not exert the same restorative effect. This in vivo study was designed to further analyze the restorative role of spleen macrophages in virus-induced immunodeficiency. Spleen cells from mice infected with the Friend-associated lymphatic leukemia virus (F-MuLV) were injected into lethally irradiated syngeneic hosts and immediately stimulated with antigen. Since the accessory functions of macrophages are highly resistant to ionizing radiations, the recipients were expected to provide the grafted cells with a supply of splenic accessory cells adequate to restore their immune functions. The primary antibody response of transferred cells was evaluated. Under these conditions, not only spleen macrophages but also peritoneal cells failed to restore the immune reactivity of infected cells, indicating that macrophages alone cannot overcome F-MuLV-induced immunodeficiency in irradiated hosts. Furthermore, irradiated and optimally reconstituted mice proved more susceptible than normal animals to the immunodepressive effect of the virus. These data suggest that additional mechanisms of immunosuppression may operate in irradiated mice and contribute to FLV-induced immunodeficiency. This model, however, may be a sensitive tool for investigating the subtle functional influences that certain viruses exert on the immune system.