Importance Whether traumatic brain injury (TBI) is a risk factor for posttraumatic stress disorder (PTSD) has been difficult to determine because of the prevalence of comorbid conditions, overlapping symptoms, and cross-sectional samples. OBJECTIVE To examine the extent to which self-reported predeployment and deployment-related TBI confers increased risk of PTSD when accounting for combat intensity and predeployment mental health symptoms. DESIGN, SETTING, AND PARTICIPANTS As part of the prospective, longitudinal Marine Resiliency Study (June 2008 to May 2012), structured clinical interviews and self-report assessments were administered approximately 1 month before a 7-month deployment to Iraq or Afghanistan and again 3 to 6 months after deployment. The study was conducted at training areas on a Marine Corps base in southern California or at Veterans Affairs San Diego Medical Center. Participants for the final analytic sample were 1648 active-duty Marine and Navy servicemen who completed predeployment and postdeployment assessments. Reasons for exclusions were nondeployment (n = 34), missing data (n = 181), and rank of noncommissioned and commissioned officers (n = 66). MAIN OUTCOMES AND MEASURES The primary outcomewas the total score on the Clinician-Administered PTSD Scale (CAPS) 3 months after deployment. RESULTS At the predeployment assessment, 56.8%of the participants reported prior TBI; at postdeployment assessment, 19.8%reported sustaining TBI between predeployment and postdeployment assessments (ie, deployment-related TBI). Approximately 87.2%of deployment-related TBIs were mild; 250 of 287 participants (87.1%) who reported posttraumatic amnesia reported less than 24 hours of posttraumatic amnesia (37 reported -24 hours), and 111 of 117 of those who lost consciousness (94.9%) reported less than 30 minutes of unconsciousness. Predeployment CAPS score and combat intensity score raised predicted 3-month postdeployment CAPS scores by factors of 1.02 (P < .001; 95%CI, 1.02-1.02) and 1.02 (P < .001; 95%CI, 1.01-1.02) per unit increase, respectively. Deployment-related mild TBI raised predicted CAPS scores by a factor of 1.23 (P < .001; 95% CI, 1.11-1.36), and moderate/severe TBI raised predicted scores by a factor of 1.71 (P < .001; 95%CI, 1.37-2.12). Probability of PTSD was highest for participants with severe predeployment symptoms, high combat intensity, and deployment-related TBI. Traumatic brain injury doubled or nearly doubled the PTSD rates for participants with less severe predeployment PTSD symptoms. CONCLUSIONS AND RELEVANCE Even when accounting for predeployment symptoms, prior TBI, and combat intensity, TBI during the most recent deployment is the strongest predictor of postdeployment PTSD symptoms. Copyright 2014 American Medical Association. All rights reserved.