Immunocompetent cell functions were evaluated in mice infected with a preparation of Friend leukemia virus complex (FV) that induces spleen focus formation and polycythemia. FV infection did not impair graft-versus-host reactions, irrespective of whether donor or host mice were infected. Also, alloantigen-sensitive units, which proliferate on exposure to foreign histocompatibility antigens, were not impaired by FV infection. Cells responsible for rejection of hematopoietic allografts in irradiated mice were similarly unaffected. Antigen-sensitive units of lymph nodes responsive to sheep red-blood cell antigens and leading to the formation of hemolytic plaque-forming cells were suppressed by FV infection. The thymic component of antigen-sensitive units, called antigen-reactive cells, was not functionally impaired. However, marrow precursors of plaque-forming cells were markedly suppressed by FV infection. Therefore, FV infection selectively affected precursors of humoral antibody-producing cells. Suppression apparently did not require continued presence of virus, since this effect was detected in infected marrow cell preparations after incubation with Friend antiserum. Immunosuppression was unaffected by previous adrenalectomy, which suggested that the effect was not mediated by adrenal hormones. Cortisol, which also suppresses marrow precursors of plaque-forming cells, enhanced spleen focus formation in susceptible mice. Thus interaction between FV and immunocompetent cells analogous to these precursors was not required for viral induction of erythropoiesis. C57BL/10 mice, genetically refractory to most strains of FV, were not made susceptible to spleen focus formation by prior treatment with cortisol. Therefore, the cellular basis for this genetic refractoriness to FV does not reside in immunocompetent precursors, but probably resides in erythropoietic “target” cells.