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An increase in mortality has been reported with early intubation in severe traumatic brain injury, possibly due to suboptimal ventilation. This analysis explores the impact of early ventilation on outcome in moderate to severe traumatic brain injury.Retrospective, registry-based analysis.This study was conducted in a large county trauma system that includes urban, suburban, and rural jurisdictions.Nonarrest trauma victims with a Head Abbreviated Injury Score of ≥3 were identified from our county trauma registry.Intubated patients were stratified into 5 mm Hg arrival Pco2 increments. Logistic regression was used to calculate odds ratios for each increment, adjusting for age, gender, mechanism of injury, year of injury, preadmission Glasgow Coma Scale score, hypotension, Head Abbreviated Injury Score, Injury Severity Score, Po2, and base deficit. Increments with the highest relative survival were used to define the optimal Pco2 range. Outcomes for patients with arrival Pco2 values inside and outside this optimal range were then explored for both intubated and nonintubated patients, adjusting for the same factors as defined previously. In addition, the independent outcome effect of hyperventilation and hypoventilation was assessed.A total of 890 intubated and 2,914 nonintubated patients were included. Improved survival was observed for the arrival Pco2 range 30–49 mm Hg. Patients with arrival Pco2 values inside this optimal range had improved survival and a higher incidence of good outcomes. Conversely, there was no improvement in outcomes for patients within this optimal Pco2 range for nonintubated patients after adjusting for all of the factors defined previously. Both hyperventilation and hypoventilation were associated with worse outcomes in intubated but not nonintubated patients. The proportion of arrival Pco2 values within the optimal range was lower for intubated vs. nonintubated patients.Arrival hypercapnia and hypocapnia are common and associated with worse outcomes in intubated but not spontaneously breathing patients with traumatic brain injury.