OBJECTIVEThe aim of this study was to examine the relationship between early arterial oxygenation thresholds and long-term outcome after severe traumatic brain injury (TBI).METHODSIn a post hoc analysis of a randomized trial, adults with severe TBI were classified based on exposure to different levels of arterial oxygenation as measured using the average of arterial partial pressure of oxygen (PaO₂) values obtained within 24 hours of admission. Potentially important PaO₂ thresholds were defined a priori. The primary outcome was Glasgow Outcome Scale–Extended (GOSE) score at 6 months. Secondary outcomes were cognitive outcomes measured using a battery of 9 neuropsychological tests administered at 6 months, and 6-month mortality.RESULTSIn adjusted analyses, oxygenation thresholds of 150 and 200 mm Hg were associated with better functional outcome at 6 months (adjusted OR for better functional outcome on GOSE 1.82 [95% CI 1.12–2.94] and 1.59 [95% CI 1.06–2.37], respectively) and improved cognitive outcome at 6 months (adjusted beta coefficients for better cognitive percentile across 9 neuropsychological tests: 6.9 [95% CI 1.3–12.5] and 6.8 [95% CI 2.4–11.3], respectively). There was no significant association between oxygenation level and 6-month mortality except at a PaO₂ threshold of 200 mm Hg (OR for death 0.36, 95% CI 0.18–0.71). Higher or lower oxygenation thresholds were not associated with functional or cognitive outcome.CONCLUSIONSIn this observational study, the relationship between early arterial oxygenation and long-term functional and cognitive TBI outcomes appears to be U-shaped. Mild levels of hyperoxemia within the first 24 hours after injury were associated with better long-term functional and cognitive outcomes. These findings highlight the importance of examining balanced oxygen supplementation as a potential strategy to improve TBI outcomes in future research.