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Catecholamine surge after traumatic brain injury (TBI) is associated with infectious morbidity and potentially preventable mortality. Previous studies have supported the protective effect of beta-adrenergic blockade in patients with TBI. We hypothesize that suppression of the catecholamine surge in multiple-injured TBI patients with beta-adrenergic blockade decreases mortality.The trauma registry at an urban Level I trauma center was queried for blunt TBI from June 1, 2003, to December 31, 2007. Patients who received more than one dose of beta-blockers (BB) were identified by a review of the hospital pharmacy order database. χ2 and Student's t tests were used where appropriate. After adjusting for age, injury severity score, admission Glasgow Coma Score, and transfusions multivariable logistic regression was performed to analyze whether receiving BB was protective in patients sustaining TBI.A total of 2,601 patients were admitted with blunt TBI during the study period. Of these, 506 patients (20%) received BB. Despite higher age (51 years vs. 38 years, p < 0.0001) and more severe head injury (head Abbreviated Injury Scale score 4.14 vs. 3.81, p < 0.0001), there was no difference in mortality (15% vs. 16%). Multivariable logistic regression identified BB as protective in patients sustaining head injury (odds ratio, 0.347; confidence interval, 0.246–0.490), when compared with those who did not receive BB, reducing mortality by 65%.BB are associated with significantly reduced mortality in patients with TBI. This simple, inexpensive intervention may have a profound effect on mortality in this population of injured patients and requires further prospective study.