The cellular mechanism by which the stem cell differentiates toward an individual myeloid lineage is unknown. To determine whether lineage-specific cytokines are involved in stem cell determination, murine bone marrow cells were infected with a retroviral vector carrying a murine erythropoietin receptor (EpoR) cDNA. Infected marrow cells were transplanted into lethally irradiated syngeneic recipient mice, and the effect of Epo was studied on EpoR-expressing pluripotent stem cell determination. The graft contained, among myeloid cells, around 100 CFU-S12, half of which were retrovirally infected. One month after grafting, the bone marrow of mice reconstituted with EpoR-infected cells contained 50 times more infected multipotent progenitors than mice reconstituted with control bone marrow cells. However, this number returned to normal 45 days after the graft. No variation was observed in peripheral blood, bone marrow, and spleen cellularities or in committed progenitors in the bone marrow and in the spleen when Neo or EpoR reconstituted mice were assayed. When Epo was delivered into reconstituted mice one month after grafting, Epo had no differential effect in EpoR or Neo reconstituted mice. This study emphasizes the in vivo Epo proliferative response of multipotent progenitors expressing a normal EpoR gene and shows that, in vivo as in vitro, the differentiation of these multipotent progenitors is not preferentially oriented toward erythropoiesis.