In order to further investigate the dependency of the production of erythropoietin (Epo) on the renal O2 supply, experiments were carried out in the isolated perfused rat kidney (IPRK). The kidneys were perfused with a substrate enriched Krebs-Henseleit solution containing 60 g/l bovine serum albumin at a constant perfusion pressure of 100 mmHg. When the kidneys were perfused at an arterial pO2 of 720 or 150 mmHg (hematocrit 5%), Epo production measured by RIA was very low (0.1-0.2 U/g kidney after 3 h of perfusion). At a pO2 of 20 mmHg, Epo production increased markedly up to 0.9 U/g kidney. However, the production of Epo was little affected by changes in the hematocrit of the perfusion medium from zero to 40%, even if severe anemia was mimicked. These results indicate that Epo production in the IPRK is mainly under the control of the arterial pO2.