This study used an electrochemical O2. sensor to investigate the effects of hyperoxia on generation of the superoxide radical (O2.) in the jugular vein during forebrain I/R in rats. Twenty-eight male Wistar rats were allocated to a sham group (n = 7; sham-treated rats with inspired oxygen fraction [FiO2] of 0.4), a hemorrhagic shock and reperfusion (HS/R) group (n = 7; HS without carotid artery occlusion and reperfusion with FiO2 of 0.4), a normoxia group (n = 7; forebrain ischemia produced by bilateral carotid arteries occlusion with HS and reperfusion with FiO2 of 0.4), and a hyperoxia group (n = 7; forebrain ischemia with FiO2 of 0.4 and reperfusion with FiO2 of 1.0). The jugular venous O2. current was measured for 10 min during forebrain ischemia and for 120 min after reperfusion. The O2. current increased gradually during forebrain ischemia in the three groups other than the sham group. Immediately after reperfusion, the current showed a marked increase in the normoxia group and a pronounced decrease in the hyperoxia group. Levels of brain and plasma malondialdehyde, high-mobility group box 1 protein, and intercellular adhesion molecule 1 were significantly attenuated in the hyperoxia group relative to those in the normoxia group. In conclusion, hyperoxia suppressed jugular venous O2. generation and malondialdehyde, high-mobility group box 1, and intercellular adhesion molecule 1 in the brain and plasma in the acute phase of cerebral I/R. Thus, the administration of 100% oxygen immediately after reperfusion suppresses oxidative stress and early inflammation in cerebral I/R.