Cerebral edema caused by vascular leakage is a major problem in various injuries of the CNS, such as stroke, head injury and high-altitude illness. A common feature of all these disorders is the fact that they are associated with tissue hypoxia. Hypoxia has been suggested to be a major pathogenic factor for the induction of vascular leakage in the brain. The objective of the present study was to evaluate potential of seabuckthorn (SBT) (Hippophae rhamnoides L.) seed oil in curtailing hypoxia induced transvascular fluid leakage in brain of hypoxia-exposed rats. Exposure of animals to hypobaric hypoxia (9144 m, 5h) caused a significant increase in the transvascular leakage studied by measuring water content and leakage of sodium fluorescein dye in the brain. Hypoxic stress also significantly enhanced the oxidative stress markers such as free radicals and malondialdehyde and it accompanied with decreased levels of antioxidants such as glutathione, glutathione peroxidase and superoxide dismutase. Pretreatment of animals with SBT seed oil significantly restricted the hypoxia induced increase in fluorescein dye leakage suggesting protection against hypoxia induced transvascular leakage in the brain. Hypoxia induced increase in the levels of free radicals and malondialdehyde were significantly lowered after SBT pretreatment. The SBT seed oil pretreatment also resulted in the significantly improved hypoxic tolerance as evidenced by increased hypoxic gasping time and survival time and decreased plasma catecholamine levels, as compared to hypoxic animals. These observations suggest that SBT seed oil possesses significant hypoxia protection activity and curtailed hypoxia induced enhanced vascular leakage in the brain.