Traumatic brain injury (TBI) is a devastating condition which continues to exert an overarching problem of high mortality and poor outcomes on those with this condition. Preclinical and clinical investigations strongly indicate that HBO2 is physiologically active in reducing brain injury and improving outcomes in severe TBI. However, prior to a definitive efficacy study, important information is required regarding optimizing the HBO2 treatment paradigm instituted in terms of pressure and frequency of HBO2 treatments and whether NBH enhances the clinical effectiveness of the HBO2 treatment. Based upon this promising evidence, the proposed project will be a randomized, prospective, multicenter, adaptive dose-finding clinical trial investigating the use of HBO2 treatment for patients with severe TBI. The primary objective will be to determine the most effective hyperoxia dose schedule without producing oxygen toxicity and clinical complications. Based on the sliding dichotomized GOS, the study aims to select the combination of treatment parameters (pressure and intervening NBH) that is most likely to demonstrate improvement at 6 months. Secondly, the trial also aims to determine whether there is a > 50% probability of hyperoxia treatment demonstrating improvement in the rate of good neurological outcome versus control in a subsequent confirmatory trial; and to inform decisions on proceeding to, and optimizing a subsequent confirmatory trial. The trial will be conducted in the Neurological Emergencies Treatment Trials network. This project is being submitted as two bundled grant applications for the Clinical Coordinating Center (at the University of Minnesota and the University of Michigan) and the Statistical and Data Management Center (at the Medical University of South Carolina).