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Although early intubation to prevent the mortality that accompanies hypoxia is considered the standard of care for severe traumatic brain injury (TBI), the efficacy of this approach remains unproven.Patients with moderate to severe TBI (Head/Neck Abbreviated Injury Scale [AIS] score 3+) were identified from our county trauma registry. Logistic regression was used to explore the impact of prehospital intubation on outcome, controlling for age, gender, mechanism, Glasgow Coma Scale score, Head/Neck AIS score, Injury Severity Score, and hypotension. Neural network analysis was performed to identify patients predicted to benefit from prehospital intubation.A total of 13,625 patients from five trauma centers were included; overall mortality was 22.9%, and 19.3% underwent prehospital intubation. Logistic regression revealed an increase in mortality with prehospital intubation (odds ratio, 0.36; 95% confidence interval, 0.32–0.42; p < 0.001). This was true for all patients, for those with severe TBI (Head/Neck AIS score 4+ and/or Glasgow Coma Scale score of 3–8), and with exclusion of patients transported by aeromedical crews. Patients intubated in the field versus the emergency department had worse outcomes. Neural network analysis identified a subgroup of patients with more significant injuries as potentially benefiting from prehospital intubation.Prehospital intubation is associated with a decrease in survival among patients with moderate-to-severe TBI. More critically injured patients may benefit from prehospital intubation but may be difficult to identify prospectively.