Exposure to hypoxia results in an increase in the plasma erythropoietin (Ep) content to a peak level in 10-12 h. If hypoxia is discontinued before maximum plasma Ep concentrations are reached, then the plasma Ep level continues to rise before it declines toward normal. To clarify this phenomenon, we determined the Ep level in the plasma and kidneys at various times after rats that had been exposed to 0.42 atm returned to ambient pressure. The plasma Ep level 2 h after hypoxia was 4-5 times as high as it was immediately after hypoxia and then gradually declined. The Ep content of the kidneys rose for only 1 h after which it rapidly fell to an undetectable level. The most plausible interpretation of this data is that renal Ep production decelerates rapidly within 1 h after return to ambient pressure, but plasma Ep levels continue to rise because of the release of preformed Ep into the plasma. Experiments were also performed to determine whether an increased plasma Ep level inhibits the production or secretion of Ep. Three different types of experiments were performed in which the plasma Ep level was increased by intravenously injecting a large amount of Ep prior to, during, or after exposure to hypoxia and determining its effect on the plasma Ep activity from 15 min to 4 h after injection. In all experiments the plasma and renal Ep levels rose comparably in Ep-treated and control rats during exposure to hypoxia. The data do not support the hypothesis that a rise in the plasma Ep level inhibits Ep production or secretion into the plasma.