Using a modified method of focal ischemic preconditioning (FIP) followed by permanent middle cerebral artery occlusion (MCAO), we studied the effects of ischemic tolerance on infarct volume. The FIP was achieved by obstructing the blood flow into the MCA using miniature clamps at two points simultaneously. The first point was proximal to its origin and the second was where it intersects the middle cerebral vein. In rats subjected to three short conditioning periods (3 x 3 min with 7 min reperfusion between occlusions), there were significant reductions in the infarct volume in the cerebral cortex induced by the subsequent MCAO in FIP-treated rats compared with sham-operated controls. This rapid FIP-induced ischemic tolerance to subsequent MCAO occurred within 1 day and lasted for 5 days. Tissue lipid peroxidation in the cortex was significantly reduced for up to 2 days after FIP. In contrast, lipid peroxidation increased rapidly after MCAO. A significant reduction in this increase was observed in FIP-treated rats, suggesting a correlation with the subsequent reduction in the infarct volume.