Background: Traumatic brain injury (TBI) caused by a high-speed transportation accident results in a mechanism of injury commonly described as diffuse axonal injury (DAI), which is associated with a reduction in dopamine turnover in the brain. Because of its affect on both dopamine and N-methyl-D-aspartate (NMDA) channels, amantadine has been the subject of considerable interest and clinical use in acute TBI. Participants: In this study, 35 subjects, who had a TBI in a transportation accident and were initially seen with a Glasgow Coma Scale score of 10 or less within the first 24 hours after admission, were randomly assigned to a double-blind, placebo-controlled, crossover design trial. Main Outcome Measures: Amantadine, 200 mg, or placebo was each administered for 6 weeks (12 weeks total) to patients who were recruited consecutively. Results: There was an improvement in the Mini-Mental Status (MMSE) scores of 14.3 points (P = .0185), Disability Rating Scale (DRS) score of 9.8 points (P = .0022), Glasgow Outcome Scale (GOS) score of 0.8 points (P = .0077), and in the FIM Cognitive score (FIM-cog)™ of 15.1 points (P = .0033) in the group that received amantadine during the first 6 weeks (group 1), but there was no improvement in the second 6 weeks on placebo (P > .05). In group 2 (active drug second 6 weeks), there was an improvement in the MMSE of 10.5 points, in the DRS of 9.4 points (P = .0006), in the GOS of 0.5 points (P = .0231), and in the FIM-cog of 11.3 points (P = .0030, Wilcoxon signed rank) spontaneously in the first 6 weeks on placebo (P = .0015). However, group 2 gained a statistically significant additional 6.3 points of recovery in the MMSE (P = .0409), 3.8 points in the DRS (P = .0099), 0.5 points in the GOS (P = .4008), and 5.2 points in the FIM-cog (P = .0173, Wilcoxon signed rank) between the sixth week and the twelfth week of treatment on the active drug. Conclusions: There was a consistent trend toward a more rapid functional improvement regardless of when a patient with DAI-associated TBI was started on amantadine in the first 3 months after injury.