Objectives: Neuroprotective benefits of ethanol (EtOH) and normobaric oxygenation (NBO) were previously demonstrated in transient and permanent ischemic stroke. Here we sought to identify whether the enhanced lactic acidosis and increased expression of monocarboxylate transporters (MCTs) observed after stroke might be attenuated by single and/or combined EtOH and NBO therapies. Methods: Sprague-Dawley rats (n=96) were subjected to right middle cerebral artery occlusion (MCAO). for 2 or 4 h (transient ischemia), or 28 h (permanent ischemia) followed by 3, 24 h, or no reperfusion. Rats received: (1) either an intraperitoneal injection of saline (sham treatment), one dose of EtOH (1.5 g/kg), two doses of EtOH (1.5 g/kg at 2 h of MCAO, followed by 1.0 g/kg 2 h after 1st dose), or (2) EtOH+95% NBO (at 2 h of MCAO for 6 h in permanent ischemia). Lactate levels were detected at 3 and 24 h of reperfusion. Gene and protein expressions of MCT-1, -2, -4 were assessed by real-time PCR and western blotting. Results: A dose-dependent EtOH neuroprotection was found in transient ischemia. Following transient ischemia, a single dose of EtOH (in 2 h-MCAO) or a double dose (in 4 h-MCAO), significantly attenuated lactate levels, as well as the mRNAs and protein expressions of MCT-1, MCT-2, and MCT-4. However, while two doses of EtOH alone was ineffective in permanent stroke, the combined therapy (EtOH+95% NBO) resulted in a more significant attenuation in all the above levels and expressions. Conclusions: Our study demonstrates that acute EtOH administration attenuated lactic acidosis in transient or permanent ischemic stroke. This EtOH-induced beneficial effect was potentiated by NBO therapy in permanent ischemia. Because both EtOH and NBO are readily available, inexpensive and easy to administer, their combination could be implemented in the clinics shortly after stroke. (C) 2015 Published by Elsevier B.V.