Hypoxemia depresses cell-mediated immune functions in males, whereas proestrous females do not show such a depression. We hypothesized that elevated systemic estradiol levels in proestrous females prevent hypoxemia-induced immune depression. To study this hypothesis, male C3H/HeN mice were pretreated with 17β-estradiol (E2, 40 μg/kg body wt sc) or vehicle for 3 days before induction of hypoxemia and again immediately before induction of hypoxia. The mice were subjected to hypoxemia (95% N2-5% 02) or sham hypoxemia (room air) for 60 min, and plasma and spleen cells were collected 2 h later. In vehicle-treated mice, splenocyte proliferation and interleukin-2 and interleukin-3 production were depressed after hypoxemia. E2-pretreated animals, however, displayed no such depression in splenic T cell parameters after hypoxemia. Splenic macrophage cytokine production was also depressed in vehicle-treated mice subjected to hypoxia, whereas it was normal in E2-pretreated mice. In summary, these findings indicate that administration of E2 before hypoxemia prevented the depression of cell-mediated immune functions. Thus administration of 17β-estradiol in high-risk patients before major surgery might decrease hypoxemia-induced immune depression under those conditions.