We have reported that pretreatment with grape seed extract (GSE), a potent antioxidant, is neuroprotective. This study examined whether treatment after injury with GSE is protective. Seven-day-old rat pups had the right carotid artery ligated, and then 2.5 h of 8% oxygen. GSE (50 mg/kg) or vehicle was administered by i.p. initial injection at 5 min to 5 h after reoxygenation, with an additional three doses within 26 h after injury. Brain damage was evaluated by weight deficit of the right hemisphere at 22 d after hypoxia. Treatment at 3 h after reoxygenation reduced brain weight loss from 21.0 +/- 3.3% in vehicle-treated pups (n = 31) to 11.4 +/- 2.8% in treated pups (n = 31, p < 0.05). GSE lowered body temperature, but reduced brain injury even when body temperature was controlled. GSE reduced neurofunctional abnormalities caused by the hypoxia-ischemia (HI). GSE reduced a HI induced increase in 8-isoprostaglandin F2alpha (8-isoPGF2alpha) and reduced an HI-induced increase in the proapoptotic protein c-jun in the brain cortex. GSE up to 3 h after reoxygenation reduces brain injury in rat pups, probably by suppressing lipid peroxidation and the proapoptotic protein c-jun.