The effect of hypoxia and changes in erythropoiesis on the absorption of 59Fe3+ from in situ tied-off duodenal segments was studied in the mouse. Hypoxia led to an increase in mucosal uptake within 6 h, whilst mucosal transfer was unaffected for about 20 h, suggesting independent regulation of these two processes. Hypoxia (3 d) stimulated erythropoiesis and resulted in a 2-3-fold increase in the total mucosal uptake of 59Fe. Conversely, hyperoxia (100% O2) caused a decrease in reticulocyte counts and the total mucosal uptake. The changes in the transfer of 59Fe from the mucosa to the body were more marked than changes in uptake in both hypoxia and hyperoxia. Mice subjected to subtotal nephrectomy showed a normal increase in the total mucosal uptake of 59Fe3+ following hypoxic exposure, despite the absence of any changes in the reticulocyte count. Obliteration of the erythroid tissue of animals by splenectomy and 89Sr treatment was accompanied by a marked decrease in the transfer of 59Fe from mucosa to the carcass. However, exposure of splenectomized 89Sr-treated mice to hypoxia resulted in an increase in the total mucosal uptake and carcass transfer of 59Fe, without any change in erythropoiesis. These results indicate that hypoxia enhances mucosal iron uptake by a mechanism which is independent of stimulated erythropoiesis, but that changes in the rate of erythropoiesis have an additional effect, particularly on the transfer phase of iron absorption.