Objective: To test the hypothesis that amantadine hydrochloride (AH), a NMDA antagonist and indirect dopamine receptor agonist, hastens resolution of symptoms of the posttraumatic confusional state (PTCS) observed during early recovery from severe nonpenetrating traumatic brain injury (TBI). Design: Randomized, double-blind, placebo-controlled, parallel group trial. Setting: Inpatient brain injury unit of free-standing rehabilitation hospital affiliated with the National Institute on Disability and Rehabilitation Research Traumatic Brain Injury Model Systems of Care. Participants: Consented neurorehabilitation admissions with posttraumatic confusion after initial nonpenetrating TBI ≤ 90 days earlier (n=79), randomly assigned to the AH (n=39) or placebo (n=40) groups. Group assignment was adjusted for baseline confusion severity at time of randomization. Intervention: AH 100mg twice daily or identical placebo for 14 days, or until confusion symptom resolution (if ≤14d) as measured by the Confusion Assessment Protocol (CAP). Main Outcome Measures: The primary outcome measure was confusion severity score as measured by the CAP after 14 days. The secondary outcome measures were (1) time to reach “nonconfused” CAP score; and (2) number of patients withdrawn from study due to predetermined, safety-related “escape” criteria. Results: There was no difference in the number of symptoms of PTCS, as measured by the CAP, between the AH and placebo-treated patients at day 14 of treatment (AH=2.56, placebo=2.7; Wilcoxon Mann-Whitney rank-sum test P=0.57). However, the mean difference in time to first “nonconfused” CAP score between groups approached significance (AH=7.7d, placebo=9.3d; Cox survival P=.053). No patients were withdrawn due to fulfillment of safety-related escape criteria. Conclusions: Although the natural course of symptom recovery from PTCS is favorable, these results provide tentative support to reports suggesting that AH safely hastens recovery from nonpenetrating TBI.