Oxidative stress increases delayed neuronal death in the brain following ischemia. As a consequence, many attempts to reduce the damage resulting from cerebral ischemia under more highly oxidized conditions have focused on treatments aimed at maintaining the redox equilibrium of the local environment. This study demonstrates the synergistic effects of combining treatments with alpha-lipoic acid (LA) and vitamin E (VE) as an efficient measure to reduce the damage caused by cerebral ischemia. Two oral therapeutic protocols were examined: intensive treatment (100 mg/kg LA and 140 mg/kg VE for 7 days after ischemia) and prophylactic treatment (20 mg/kg LA and 50 mg/kg VE from 30 days before infarction up to the day of sacrifice). The prophylactic treatment reduced serum lipid peroxidation, and diminished brain infarct volume by approximately 50%. Furthermore, prophylactically treated rats showed a reduction in post-ischemia neurological scores. No significant differences were found in the intensively treated group. Our data indicate that pre-ischemia administration of the LA-VE antioxidant mixture reduced the volume of brain damaged and the functional consequences of embolic infarction. These findings suggest that prophylaxis with an LA-VE mixture may be valuable in reducing cerebral damage levels in patients with a high risk of stroke.