Prior prolonged oxygen exposure is associated with some protection against ischemia-reperfusion (IR) injury to rat brain tissue, but also with toxic effects. We sought to compare the magnitude of protection offered by prolonged and intermittent oxygen pretreatments against IR injury to the rat brain. Rats were divided into four experimental groups, each of 21 animals. The first two were exposed to 95% inspired (normobaric hyperoxia, NBHO) for 4 h/day for 6 consecutive days (intermittent NBHO) or for 24 continuous hours (prolonged NBHO). The second two groups acted as controls were exposed to 21% oxygen. After 24 h, they were subjected to 60 min of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. The animals were sacrificed for assessment of infarct volume, brain edema, and blood-brain barrier (BBB) permeability, respectively. Prolonged and intermittent NBHO pretreatment reduced infarct volume by 63.3% and 73.7%, respectively, when compared to the respective NBNO groups. Intermittent NBHO (when compared to intermittent NBNO) also reduced the post-ischemic increment of brain water content significantly (81.53+/-0.8%, vs. 80.12+/-0.79%) and Evans Blue extravasation (7.49+/-2.89+/-g/g tissue vs. 3.9+/-0.79 microg/g tissue, P<0.001), while prolonged NBHO had no significant effect on brain water content (81.69+/-1.16% vs. 80.74+/-0.94%) and EB extravasations (6.48+/-2.42 microg/g tissue vs. 4.31+/-1.07 microg/g tissue). Intermittent hyperoxia had relatively more significant effects on brain edema and BBB protection. Although preconditioning with both prolonged and intermittent oxygen exposure protects rat brain tissue against IR injury, the intermittent hyperoxia could have relatively more protective effects in this regard.