The wide availability, low cost, and multiple biochemical, molecular and hemodynamic effects of hyperoxia make it ideally suited as a neuroprotective strategy. In animal studies, and in a recent pilot human study, we have documented that breathing high-flow oxygen (normobaric hyperoxia therapy or NBO) during brain ischemia confers potent neuroprotection. The benefit of NBO appears to be transient, similar to that observed in prior hyperbaric oxygen studies. However, sustained benefit does occur if NBO-treated tissue is reperfused. We believe that today, with enhanced reperfusion rates from newer therapies such as tPA, and advances in MRI that allow serial assessment of tissue ischemia-reperfusion, there exists an exciting opportunity to assess whether NBO's transient tissue-salvaging effects can be converted (via induced or spontaneous reperfusion) into sustained benefit. By preventing early ischemic cell death, NBO may be a feasible strategy to extend the narrow time window for IV tissue plasminogen activator (tPA) therapy. In this proposal we aim to extend our preliminary work in a double-blind study enrolling 150 acute (<12 hours) ischemic stroke patients over 5 years. Patients will receive NBO or Room Air for 8 hours and will undergo serial clinical examinations and diffusion-perfusion MRI (DWI/PWI). Safety and efficacy of NBO will be determined in an 'intention to treat' statistical analysis of change in NIH stroke scale scores during and after therapy. The potential synergistic benefit of NBO with reperfusion will be assessed. We will also compare MRI ischemic lesion growth and hemorrhage rates, and perform novel voxel-based analyses of DWI and PWI parameters. In year 1 we will exclude tPA-treated patients and investigate the safety of NBO with tPA in an embolic (clot-based) rodent stroke model. If the combination appears safe in rodents, and if the year 1 human data raises no safety concerns, we will expand to include tPA-treated patients. Finally, we will conduct pathological and in-vivo MRI studies in rodent stroke models to investigate whether NBO can extend the tPA time window, and to investigate NBO's effects on cerebral hemodynamics. These studies are significant because they will comprehensively test the effects of oxygen in the ischemic brain. Breathing high-flow oxygen may prove to be a simple, practical, portable, and potentially cost-effective therapy that improves stroke outcomes, either independently or by extending the time window for IV tPA.