Daily administration for 4 days of doses of methyl prednisolone acetate (MPA) ranging from 0.5 to 4.0 mg depressed erythropoiesis in normal mice; this effect was partially overcome by administration of erythropoiesis-stimulating factor (ESF). The mechanism of this inhibitory action of MPA on erythropoiesis involves: a diminution in the numbers and/or the response of hemic stem cells to ESF as seen in both normal and plethoric mice, and a depression of ESF production, noted with the higher dose level (4 mg) in mice subjected to hypoxia. The ability of MPA to counteract the erythropoiesis-stimulating effect of hypoxia was not attributable to the presence of erythropoiesis-inhibiting factors in the plasma. This was shown from the inability of plasma secured from MPA-treated mice to depress erythropoiesis in normal micr or to inhibit the action of exogenous ESF in plethoric mice.