ABSTRACT. Objective: Premised on biological evidence from animal research, recent clinical studies have, for the most part, concluded that elevated blood alcohol concentration levels are independently associated with higher survival or decreased mortality in patients with moderate to severe traumatic brain injury (TBI). This study aims to provide some counterevidence to this claim and to further future investigations. Method: Incident data were drawn from the largest U.S. trauma registry, the National Trauma Data Bank, for emergency department admission years [2002][2003][2004][2005][2006]. TBI was identifi ed according to the National Trauma Data Bank's defi nition using International Classifi cation of Diseases, Ninth Revision, Clinical Modifi cation (ICD-9-CM), codes. To eliminate confounding, the exact matching method was used to match alcohol-positive with alcohol-negative incidents on sex, age, race/ethnicity, and facility. Logistic regression compared in-hospital mortality between 44,043 alcohol-positive and 59,817 matched alcohol-negative TBI incidents, with and without causes and intents of TBI and Injury Severity Score as covariates. A sensitivity analysis was performed within a subsample of isolated moderate to severe TBI incidents. Results: Alcohol use at the time of injury was found to be signifi cantly associated with an increased risk for TBI. Including varied causes and intents of TBI and Injury Severity Score as potential confounders in the regression model explained away the statistical signifi cance of the seemingly protective effect of alcohol against TBI mortality for all TBIs and for isolated moderate to severe TBIs. Conclusions: The null fi nding shows that the purported reduction in TBI mortality attributed to positive blood alcohol likely is attributable to residual confounding. Accordingly, the risk of TBI associated with alcohol use should not be overlooked. (J. Stud. Alcohol Drugs, 73, 531-541, 2012)