We tested the hypothesis that hypoxia causes cellular oxidative stress by measuring plasma concentrations of glutathione disulfide (GSSG) in rats exposed to acute and subacute hypoxia. In awake, unanesthetized, catheter-implanted rats, exposure to 8% O2 for 10 min caused pulmonary vasoconstriction and increased plasma GSSG. This increase in plasma GSSG was reversible upon re-exposure to room air. In another group of rats exposed to 48 hours of hypobaric hypoxia (Pb 450 mmHg, equivalent to about 14,500 feet altitude), plasma GSSG, but not total glutathione, was significantly increased over control values (2.83 +/- 0.24 vs 1.84 +/- 0.14 nmol/ml, p less than 0.05). While lung tissue GSSG in high altitude-exposed rats were somewhat higher than in controls (17.4 +/- 7.0 vs 11.9 +/- 3.6 nmol/g wet lung wt.), the difference was not statistically significant. Treatment of the rats with a radical scavenger, DMSO, before altitude exposure, blocked the increase in plasma GSSG (1.86 +/- 0.16 nmol/ml). We conclude that both acute and subacute hypoxia increase plasma GSSG in rats and speculate that hypoxia induces cellular oxidative stress in vivo.