The potential for sertraline administered in the first 3 months after moderate to severe traumatic brain injury (TBI) to decrease the incidence of depression in the first year after injury was assessed in a double-blinded randomized control trial. Subjects were enrolled an average of 21 days after injury (none >8 weeks) followed by oral administration of placebo (50 subjects) or sertraline 50 mg (49 subjects) for 3 months. Subjects were not depressed at the time of study initiation. Outcome was assessed using the Hamilton Depression Rating Scale (HDRS) and the Depression Scale of the Neurobehavioral Functioning Inventory (NFI). Based on intent-to-treat and efficacy subset analyses, those receiving placebo exhibited significantly greater depressive symptoms than those receiving sertraline during the first 3 months after injury while receiving placebo/drug (10% of placebo group achieving a score of 6 or greater on the HDRS, 0% of the sertraline group; p < 0.023.). There was no significant difference in depressive symptoms during the remainder of the year between the two groups. Sertraline is effective in diminishing depressive symptoms even among those not clinically depressed while the medication is being taken. However, the results do not support the idea that administration early in recovery diminishes the expression of depressive symptoms after the drug is stopped. There is no basis from this study to assume that sertraline administered early in recovery after TBI, when neurotransmitter functioning is often altered, has ongoing effects on the serotonin system after sertraline is discontinued.