The National Brain Injury Rescue and Rehabilitation Project was established as a preliminary study to test the safety and practicality of multi-center hyperbaric oxygen administration for the post-concussive symptoms of chronic mild traumatic brain injury as a precursor to a pivotal, independent, multi-center, controlled clinical trial. This report presents the results for 32 subjects who completed a preliminary trial of hyperbaric oxygen several years before the passage of the 21st Century Cures Act. This study anticipated the Act and its reassessment of clinical research. Subjects received 40–82 one-hour treatments at 1.5 atmospheres absolute 100% oxygen. Outcome measures included repeated self-assessment measures and automated neurocognitive tests. The subjects demonstrated improvement in 21 of 25 neurocognitive test measures observed. The objective neurocognitive test components showed improvement in 13 of 17 measures. Earlier administration of hyperbaric oxygen post injury, younger age at the time of injury and hyperbaric oxygen administration, military status, and increased number of hyperbaric oxygen administrations were characteristics associated with improved outcomes. There were no adverse events. Hyperbaric oxygen was found to be safe, inexpensive and worthy of clinical application in the 21st Century model of facile data collection provided by recent research regulatory shifts in medicine. The study was approved by the ethics review committee of the Western Institutional Review Board (WIRB® Protocol #20090761).