Whereas plasma from mice, rats and tamarins subjected to hypoxia significantly augmented erythropoiesis (RBC-Fe59 incorporation values) in transfusion-induced plethoric mice, plasma from animals injected with estradiol cyclopentylpropionate (ECP) before exposure to hypoxia lacked this capacity. The ability of ECP to counteract the erythropoiesis-stimulating action of hypoxia was not due to the presence of residual biologically active estrogen in the plasma. That it was also not attributable to other blood-borne erythropoiesis-inhibiting agents evoked by the estrogen was evident because plasma from ECP-treated mice failed to 1) depress erythropoiesis in normal mice, 2)prevent the production of the erythropoiesis stimulating factor (ESF) in plethoric mice exposed to hypoxia, and 3) antagonize the erythropoietic action of exogenous ESF. The conclusion drawn is that estrogen inhibits the production of the ESF. It was further shown that, whereas the stimulatory action of androgen (testosterone cyclopentylpropionate) on erythropoiesis required the presence of the kidneys, the erythropoiesis-inhibiting effects of estrogen were evident in nephrectomized as well as in intact mice. It is suggested that estrogens inhibit erythropoiesis by suppressing the production of an extrarenal precursor of ESF which requires activation by a kidney mechanism for elaboration of the functional circulating ESF.