Resveratrol has a neuroprotective effect against cerebral ischemia. The objective of this study was to identify proteins that are differentially expressed in the cerebral cortex of vehicle- and resveratrol-treated animals during ischemic injury. Focal cerebral ischemia was induced as middle cerebral artery occlusion (MCAO) in male rats. Rats were treated with vehicle or resveratrol before MCAO, and cerebral cortex was collected 24 hr after MCAO. Cerebral cortex proteins were identified by two-dimensional gel electrophoresis and mass spectrometry. Several proteins were identified as differentially expressed between vehicle- and resveratrol-treated animals. Among these proteins, expression of peroxiredoxin-5, isocitrate dehydrogenase [NAD⁺], apolipoprotein A-I and ubiquitin carboxy terminal hydrolase L1 was decreased in the vehicle-treated group, whereas resveratrol attenuated the injury-induced decrease in expression of these proteins. However, expression of collapsing response mediator protein 2 was increased in the vehicle-treated group, whereas resveratrol prevented the injury-induced increase in the expression of this protein. These findings suggest that resveratrol modulates the expression of various proteins that associated with oxidative stress and energy metabolism in focal cerebral ischemia.