Fetal sheep produced significant amounts of erythropoietin in response to bleeding. Bilateral nephrectomy prior to bleeding failed to influence the formation of erythropoietin. Removal of the spleen, in addition to kidneys, was also without effect. Subtotal hepatectomy prior to bleeding, however, inhibited erythropoietin formation in these fetuses. In situ perfusion of the liver, but not the kidney, resulted in the appearance of significant quantities of the hormone in the perfusate. These results suggest that the liver is the primary site of erythropoietin production in the mammalian fetus.