This report confirms that the Fv-5 locus controls the types of erythropoiesis induced by Friend erythroleukemia virus (FLV) (21) and extends the study to investigate the mode of action of this locus. With the use of FLV obtained by a variety of procedures, we showed that the polycythemia spleen focus-forming component (SFFVp) was responsible for the contrasting changes of hematocrits observed in FV-Pp (polycythemia strain)-infected DBA/2 (Fv-5pp) or CBA (Fv-5aa) mice. These changes in hematocrits were found to be a direct result of the rise in circulating reticulocytes and erythrocytes in DBA/2 mice and a corresponding drop of these erythroid cells in CBA mice 2 wk after infection. Examination of the FV-P-induced cellular changes indicated that dramatic increase in erythropoietin (epo)-independent erythroid precursor (CFU-E*) cells was detected in the spleens and marrow of both strains of mice. The epo responsiveness of the CFU-E in the uninfected and FV-P-infected CBA and DBA/2 mice was also very similar. Similar to FLV-infected DBA/2 mice, the FV-P-infected CBA mice also developed tumorogenic cells (CFU-FV) relatively early after infection (4-6 wk). Study of the physiological and pathological changes in the marrows and spleens of these infected mice indicated that significant differences were found in the spleens of the two strains of mice. The percent of reticulocytes in the spleen cells of CBA mice remained between 10 and 20%, and level of the DBA/2 mice increased to approximately 50%. This higher rate of erythropoiesis was also reflected in the significantly higher rate of uptake of 59Fe in the spleens of the DBA/2 mice. These results suggest that the Fv-5 locus might control the hematocrit levels of these mice by regulating the rates of erythropoiesis in the spleen levels of these mice, probably by affecting the rate of proliferation of an erythroid cell or cells. The erythroid cell(s) affected is likely to be more mature than the erythroid progenitor, CFU-E, as the levels of CFU-E in these two strains of mice were similar. The hypothesis that Fv-5 may control the rates of proliferation of a late erythroid (cell(s) is also supported by the significantly higher spleen weights found in the infected DBA/2 (approximately 2.5 g/spleen) mice than in the CBA (approximately 1 g/spleen) strain.