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Prehospital intubation has been challenged on the grounds that it predisposes to hyperventilation, which is detrimental after traumatic brain injury (TBI), and impairs venous return in patients with hypovolemia. We sought to determine the incidence of hyperventilation among a cohort of trauma patients undergoing prehospital intubation and the impact of ventilation on outcome after severe TBI.Data were prospectively collected for all intubated trauma patients transported directly from the field for a period of 14 months (n = 574). An arrival Pco2 <30 mm Hg was termed severe hypocapnea and considered a marker of hyperventilation. Patients with a Pco2 >45 mm Hg were considered severely hypercapneic. Targeted ventilation was defined as a Pco2 between 30 and 35 mm Hg based on the Brain Trauma Foundation guidelines.The rate of severe hypocapnea was 18% and women were more likely to be hyperventilated (p < 0.05). Patients with severe hypercapnia had higher Injury Severity Scores and were more likely hypotensive, hypoxic, and acidodic (p < 0.05). Patients in the targeted ventilation range were less likely to die than were those outside the range even after excluding the severe hypercapnea group (odds ratio, 0.57; 95% confidence interval, 0.33–0.99). This effect was even greater among patients with isolated TBI (odds ratio, 0.31; 95% confidence interval, 0.10–0.96).Targeted prehospital ventilation is associated with lower mortality after severe TBI.