Background and purpose: The effect of normobaric oxygen (NBO) on apoptosis remains controversial. The present study evaluated the effect of NBO on ischemia-induced apoptosis and assessed the potential for improved outcomes by combining NBO administration with another neuroprotective agent, ethanol, in a rat stroke model. Methods: Rats were subjected to right middle cerebral artery occlusion (MCAO) for 2 h. At the onset of reperfusion, ischemic animals received either NBO (2 h duration), an intraperitoneal injection of ethanol (1.0 g/kg), or both NBO and ethanol. Extent of brain injury was determined by infarct volume, neurological deficit, and apoptotic cell death. Expression of pro- and anti-apoptotic proteins was evaluated through Western immuno-blotting. Results: Given alone, NBO and ethanol each slightly (p < 0.05) reduced infarct volume to 38% and 37%, respectively, as compared to the impressive reduction of 51% (p < 0.01) seen with combined NBO-ethanol administration. Neurologic deficits were also significantly reduced by 48% with combined NBO-ethanol therapy, as compared to lesser reductions of 24% and 23% with NBO or ethanol, respectively. Combined NBO-ethanol therapy decreased apoptotic cell death by 49%, as compared to 31% with NBO and 30% with ethanol. Similarly, combination therapy significantly increased expression of anti-apoptotic factors (Bcl-2 and Bcl-xL) and significantly reduced expression of pro-apoptotic proteins (BAX, Caspase-3, and AIE), as compared to the minimal or nil protein expression changes elicited by NBO or ethanol alone. Conclusions: In rats subjected to ischemic stroke, NBO administration salvages ischemic brain tissue through evidenced decrease in apoptotic cell death. Combined NBO therapy with ethanol administration greatly improves both degree of neuroprotection and associated apoptosis. (c) 2013 Elsevier B.V. All rights reserved.