Objective: To assess the efficacy of sertraline administered in the first 3 months after moderate to severe traumatic brain injury (TBI) in improving cognitive and behavioral outcomes. Design: Double-blind, randomized controlled trial. Setting: Academic medical center. Participants: Ninety-nine individuals randomized to placebo (n = 50) or sertraline 50 mg (n = 49) conditions. There were no group differences in age, gender, education, or severity of injury. Interventions: Participants were enrolled an average of 21 days after injury (none > 8 weeks), followed by oral administration of placebo or sertraline 50 mg for 3 months. MAIN Outcome Measures: Wechsler Memory Scale-Third Edition Logical Memory, Trail Making Test, Wechsler Adult Intelligence Scale-Third Edition Working Memory Index, Symbol-Digit Modalities Test, Wisconsin Card Sorting Test (64-item), Neurobehavioral Functioning Inventory administered 3, 6, and 12 months after the onset of injury. Results: Early administration of sertraline did not result in improved cognitive functioning during the year after injury compared with placebo administration. Those receiving placebo performed marginally better than the treatment group on a measure of executive function, but this appeared to be inauthentic. The treatment group followed expected recovery patterns based on existing literature. The placebo group performed better than expected on some measures, primarily due to differential dropout. Conclusions: Sertraline does not appear to prevent development of cognitive and behavioral problems following TBI, although this does not negate evidence for the treatment (as opposed to prophylactic) role of sertraline to address emotional and neurobehavioral problems in individuals with TBI. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.