The influence of the pancreas on renal and extrarenal erythropoietin (Ep) production and on the elaboration of the hepatic erythropoietic factor (HEF) was studied in these experiments. Insulin was found to elevate Ep levels in the anephric hypoxic rat when compared to controls, whereas glucagon treatment augmented the hepatic Ep response to hypoxia in the subtotally hepatectomized (hepx) animal while lowering it in the renal intact rat. Production of experimental diabetes either through chemical induction by alloxan or following pancreatectomy diminished the Ep response in all groups tested. Treatment with antiglucagon caused an elevation in the Ep response to hypoxia in the intact rat but lowered Ep levels in the hepx animal. In addition, glucagon and a synthetic hepatotrophic agent (L-histidyl L-lysine acetate) stimulated HEF production in the hepx rat, although none of the agents tested were capable of enhancing HEF levels in the intact rat.