The study compared effects of different hypobaric hypoxia regimens (14% O2, 10.5% O2, and 8% O2; 1 hour; 15 days) on parameters of the glutathione system, intensity of free radical oxidation, and intensity of lipid peroxidation in cerebral cortex (CC) of rats with different, genetically predetermined resistance to acute hypoxia. In normoxia, baseline concentrations of oxidized glutathione (0.155 ± 0.011 nmol/mg protein) and hydroperoxide metabolites (50.4 ± 2.62 cumene hydroperoxide equivalents/g tissue) were 20% lower in CC of low-resistance (LR) rats than in high-resistance (HR) rats (0.191 ± 0.013 nmol/mg protein; 63.0 ± 3.46 cumene hydroperoxide equivalents/g tissue, respectively). Baseline activities of the glutathione cycle enzymes, glutathione peroxidase (31.2 ± 1.59 nmol/min/mg protein) and glutathione reductase (28.5 ± 1.49 nmol/min/mg protein), were 30% lower in LR rat CC than in HR rat CC (47.0 ± 2.41; 433 ± 2.26 nmol/min/mg protein, respectively). These data suggested more efficient antioxidant defense of CC tissue in LR rats than in HR rats. The phenotypic difference in CC tissue redox properties between two rat phenotypes remained in hypoxia. The efficiency of glutathione system in regulation of CC redox homeostasis was shown to depend on both severity and duration of hypoxic exposures and on individual tolerability of hypoxia, i.e., this efficiency was genetically predetermined. The glutathione system maintains its regulatory properties in a broader range of lowered pO2 values and during longer hypoxic exposures. in LR rat CC than in HR rat CC. For this reason, activation of free radical processes and development of oxidative stress induced by single or repeated hypoxic exposures are prevented or alleviated in LR rat CC but not in HR rat CC. The obtained data strongly justify the need for selection of hypoxic exposure regimens for therapeutic hypoxic preconditioning. Apparently the hypoxic exposures not associated with signs of oxidative stress should be considered optimum.