OBJECTIVE To investigate the relationship between oxygenation and short-term outcomes in patients with traumatic brain injury (TBI). DESIGN Logistic regression analysis was used to determine whether average high (>200 mm Hg) or low (<100 mm Hg) PaO2 levels within the first 24 hours of hospital admission correlated with patient outcomes relative to patients with average PaO2 levels between 100 and 200 mm Hg. SETTING Level 1 trauma center. PATIENTS We retrospectively reviewed 1547 consecutive patients with severe TBI who survived past 12 hours after hospital admission. MAIN OUTCOME MEASURES We measured mortality, intensive care unit length of stay, hospital length of stay, and discharge Glasgow Coma Scale (GCS) score. RESULTS Of the 1547 patients, 77% were male and 89% sustained blunt trauma. Mean (SD) age, admission GCS score, and Injury Severity Score were 41.3 (20.6) years, 8.3 (4.7), and 31.9 (12.5), respectively. Mean (SD) intensive care unit length of stay and hospital length of stay were 8.7 (10.5) days and 13.8 (13.7) days, respectively. Mean (SD) discharge GCS score was 10.1 (4.7). The mortality rate was 28%. After controlling for age, sex, Injury Severity Score, mechanism of injury, and admission GCS score, patients with high PaO2 levels had significantly higher mortality and lower discharge GCS scores than patients with a normal PaO2 (P < .05). Patients with low PaO2 levels also had increased mortality (P < .05). CONCLUSIONS Hyperoxia within the first 24 hours of hospitalization is associated with worse short-term functional outcomes and higher mortality after TBI. Although the mechanism for this has not been completely elucidated, it may involve hyperoxia-induced oxygen-free radical toxicity with or without vasoconstriction. Hyperoxia and hypoxia were found to be equally detrimental to short-term outcomes in patients with TBI. A narrower therapeutic window for oxygenation may improve mortality and functional outcomes.