In response to concerns by Critical Care Air Transport Teams that prolonged flights during aeromedical evacuation (AE) of neurotrauma patients might worsen neurologic outcomes, the effects of exposing rats to hypobaria (HB) at different times after mild or moderate traumatic brain injury (TBI) were investigated. Following either impact-induced moderate TBI or blast-induced mild TBI, histologic and neurologic markers of injury were worsened by 6 hours HB (=8,000 feet altitude), initiated at 6, 24, or 72 hours after injury or 6-7 days after injury. Brain injury was also worse when rats were exposed to 100% oxygen (O2) compared to 21-28% O2 during HB. Exposure to two flights at 24 hours and 72 hours caused more damage than one flight at either of these times following impact TBI but not blast TBI. Following impact TBI, administration of CR8, an anti-inflammatory cell cyclin-dependent kinase inhibitor, improved behavioral and histologic outcomes. TBI and subsequent HB were accompanied by elevated levels of serum microparticles, which could contribute to systemic inflammation. Changes in gene expression in the brain following blast TBI and HB suggest that drugs that trigger an increase in the expression of cytoprotective genes could be used to improve outcomes in these paradigms.