Inspired oxygen (FiO2) was manipulated during the early reperfusion period after global cerebral ischemia (four-vessel occlusion of 20 or 30 min duration) in anesthetized rats. The goal was to determine whether oxygen availability during the early reperfusion period alters recovery of mitochondrial redox state and evoked electrical activity. The effectiveness of post-ischemic oxygen treatment was monitored at the tissue level with oxygen sensitive microelectrodes, and at the mitochondrial level by reflection spectrophotometry of the redox state of cytochrome oxidase. Transiently decreasing FiO2 from 0.3 to 0.15 limited reperfusion-induced hyperoxygenation and post-ischemic mitochondrial hyperoxidation (PIMHo). Evoked potential recovery was improved by this treatment after 20 min ischemia but not after 30 min ischemia. Increasing FiO2 from 0.3 to 1.0 exacerbated PIMHo and tissue hyperoxygenation. Transient elevation of tissue oxygen tension after 30 min of global ischemia inhibited recovery of evoked potentials. These data suggest that a period of heightened vulnerability to oxidative stress occurs within the first 10 min of reperfusion after global ischemia. This period is characterized by tissue hyperoxygenation and mitochondrial hyperoxidation. Limiting oxygen availability during this period may improve the outcome while conversely elevating oxygenation may be detrimental.