Hypoxia induces a wide range of deleterious effects at the cellular level due to an increased production of reactive oxygen species (ROS). Polyphenols from grape seeds, which are potent antioxidants might protect the brain against oxidative stress produced by hypobaric hypoxia. The brain effects of three doses of grape seed extract intraperitoneally (i.p.) administered in rats after exposure to hypobaric hypoxia corresponding to 5500 m altitude were investigated. Some oxygen and nitrogen reactive species, inflammatory cytokine (IL-6) and molecules involved in angiogenesis (vascular endothelial growth factor [VEGF], matrix metalloproteinase 2 [MMP2], and tissue inhibitors of metalloproteinase 1 [TIMP1]) were determined. Forty-two rats were divided in seven groups: group 1, control; groups 2, 3, and 4 were exposed to hypobaric hypoxia for 24 h in a hypobaric chamber; groups 5, 6, and 7 were exposed to hypobaric hypoxia for 5 days. After returning to normal atmospheric pressure, rats from groups 2 and 5 were sacrificed without other treatment. Animals from groups 3 and 6 were i.p treated with carboxymethyl cellulose (CMC) vehicle and those from groups 4 and 7 were i.p. treated with grape seed extract (GSE) (50 mg gallic acid equivalents/kg body weight in 0.5 mL CMC suspension/animal). The treatment was applied at 2, 24, and 72 h from returning to normoxia. Hypobaric hypoxia produced increased brain levels of ROS, nitric oxide (NO), IL-6, and VEGF after both time intervals (P<.05). The MMP2 concentration was significantly increased in groups treated only with vehicle, whereas TIMP1 was slightly changed. GSE produced a significant reduction of ROS and NO levels proving its antioxidant capacity. It also decreased IL-6 and MMP2 concentrations to values similar to controls. The VEGF concentration was also significantly reduced. These effects are indicative for anti-inflammatory and antiangiogenic properties of GSE.