PRIMARY OBJECTIVE To evaluate the effectiveness of rivastigmine for chronic sequels of traumatic brain injury (TBI). RESEARCH DESIGN Randomized, placebo-controlled, double-blind crossover trial. METHODS AND PROCEDURES Of 772 outpatients with TBI treated during 1993-2002, all eligible patients were contacted and 102 patients volunteered. They were randomized to receive either rivastigmine (Exelon) or placebo. The study included two periods with titration to the highest tolerated or maximum dose (12 mg rivastigmine daily) and a maintenance period of 8 weeks, separated by a 4-week washout. Computerized neuropsychological testing and standardized clinical interviews were used to assess the outcome. MAIN OUTCOMES AND RESULTS Sixty-nine patients completed the study and 17 withdrew because of adverse effects. In two measures of computerized testing (subtraction test, p = 0.034 and correct answers in the 10-15 minute vigilance test, p = 0.048) rivastigmine was better than placebo. The clinical interviews did not yield significant results. After the study, 45% of patients considered rivastigmine beneficial compared to 20% with placebo. CONCLUSIONS A weak trend favouring rivastigmine for chronic symptoms of TBI was observed. The clinical significance of the results and the problems in conducting drug trials for chronic TBI symptoms are discussed.