In this study, we investigated the effects of severe hypobaric hypoxia (SH) and severe hypobaric hypoxia accompanied by postconditioning using mild hypobaric hypoxia (PostC) on the glutathione-dependent antioxidant system in the rat hippocampus and neocortex. SH (3 h, 180 mmHg, 5% O2) led to oxidative stress that was associated with a decrease in the total glutathione level, as well as in antioxidant capacity. PostC (2 hours, 360 mmHg, 10% O2) led to incomplete recovery of the total glutathione level and up-regulated glutathione peroxidase activity. In the neocortex, SH did not lead to the development of posthypoxic pathology. A small decrease in total glutathione, glutathione peroxidase activity, and antioxidant capacity on the 1st day after SH was corrected by the 2nd day. In contrast, glutathione reductase activity decreased by the 4th day after exposure to SH. PostC led to a consistent decrease in the total glutathione level but normalized glutathione reductase activity. We found that the studied brain structures develop a specific response to SH. In the hippocampus, SH led to oxidative stress, whereas the neocortex was not affected by exposure to SH. Partial differences between brain areas are based on better antioxidant defense of the neocortex in comparison with the hippocampus. PostC corrects posthypoxic pathology in the hippocampus with involvement of the glutathione-dependent antioxidant system. In the neocortex, PostC did not lead to a significant biochemical response. Keywords: glutathione-dependent antioxidant system, antioxidant capacity, hippocampus, neocortex, severe hypoxia, postconditioning by mild hypobaric hypoxia