ESF titers were determined in 99 patients of various stages of chronic renal failure, by using the fetal mouse liver cell bioassay. Of these patients 45 were receiving conservative therapy and 54 on maintenance hemodialysis. ESF levels were significantly below normal in both groups of patients. A significant inverse relationship was found between hemoglobin concentration and ESF level in the predialysis patients with chronic glomerulonephritis. No correlation was found between both parameters in the predialysis patients with chronic nonglomerular renal disease. A significant positive correlation was found between hemoglobin concentration and ESF level in nephric dialysis patients who were transfusion independent. Transfusion-dependent nephric dialysis patients had lower hemoglobin concentrations and lower ESF levels before transfusion than did nephric dialysis patients who were transfusion independent. In nephric dialysis patients ESF levels fell sharply after blood transfusion, whereas in anephric dialysis patients such a physiologic ESF response was not found. It was concluded that despite the presence of an absolute ESF deficiency in all anemia uremic patients, this anemia cannot be explained by ESF deficiency alone. The increasing degree of anemia found in predialysis patients with deteriorating renal function appears to be primarily caused by factors other than ESF deficiency, the most likely being accumulation of uremic inhibitors of erythropoiesis. In dialysis patients in whom inhibitor levels are relatively homogeneous, the degree of anemia appears to be directly related to the residual capability of the kidney or the extrarenal sites to produce ESF.