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BACKGROUND Hypotension and hypoxemia worsen traumatic brain injury outcomes. Hyperoxic resuscitation is controversial. The authors proposed that hyperoxia would improve hemodynamics and neuronal survival by augmenting oxygen delivery despite increased oxidative stress and neuroinflammation in experimental combined controlled cortical impact plus hemorrhagic shock in mice. METHODS Adult C57BL6 mice received controlled cortical impact followed by 35 min of hemorrhagic shock (mean arterial pressure, 25-27 mmHg). The resuscitation phase consisted of lactated Ringer's boluses titrated to mean arterial pressure greater than 70 mmHg. Definitive care included returning shed blood. Either oxygen or room air was administered during the resuscitation phases. Brain tissue levels of oxidative stress and inflammatory markers were measured at 24 h and hippocampal neuronal survival was quantified at 7 days. RESULTS Hyperoxia markedly increased brain tissue oxygen tension approximately four- to fivefold (n = 8) and reduced resuscitation fluid requirements approximately 15% (n = 53; both P < 0.05). Systemic and cerebral physiologic variables were not significantly affected by hyperoxia. Hippocampal neuron survival was approximately 40% greater with oxygen versus room air (n = 18, P = 0.03). However, ascorbate depletion doubled with oxygen versus room air (n = 11, P < 0.05). Brain tissue cytokines and chemokines were increased approximately 2- to 20-fold (n = 10) after combined controlled cortical impact injury plus hemorrhagic shock, whereas hyperoxia shifted cytokines toward a proinflammatory profile. CONCLUSIONS Hyperoxic resuscitation of cortical impact plus hemorrhagic shock reduced fluid requirements and increased brain tissue oxygen tension and hippocampal neuronal survival but exacerbated ascorbate depletion and neuroinflammation. The benefits of enhanced oxygen delivery during resuscitation of traumatic brain injury may outweigh detrimental increases in oxidative stress and neuroinflammation.