Isolated dog kidneys were perfused with blood at normal and reduced oxygen tensions with and without cobalt. Erythropoietin titers were found to be significantly increased in the blood perfusates from kidneys perfused with blood at lowered oxygen tensions, while no change in erythropoietin was seen when kidneys were perfused with blood at a normal oxygen tension. Cobalt produced significant increases in erythropoietin levels in the perfusates with normal as well as reduced oxygen tension blood, but its effect was more marked when the kidneys were perfused with hypoxic blood. Renal blood flows were higher when the dogs’ own lungs were used to oxygenate the blood than when a bubble oxygenator was used in the system. However, hypoxic blood resulted in significant increases in erythropoietin production in both systems. In studies of the kidney histology from both perfusion systems with hypoxic and normal oxygen tension blood, most of the kidneys demonstrated varying degrees of glomerular congestion. No correlation was found between erythropoietin elaboration and renal congestion or other degenerative cellular changes in the kidney. Therefore, it does not seem likely that erythropoietin produced in the isolated perfused kidney is due to histologic damage to renal cells. These findings support the concept that increased erythropoietin production in the isolated perfused kidney in response to cobalt or hypoxic blood is a direct effect of these stimuli on the kidney.