The aim of this study was to evaluate the efficacy and tolerability of tiagabine in adult patients with post-traumatic stress disorder (PTSD). This 12-week, multicenter, double-blind study randomized patients to receive either tiagabine or placebo. Tiagabine (administered in divided doses) was initiated at 4 mg/d (2 mg BID) and individually titrated of up to 4 mg/d weekly to a maximum dose of 16 mg/d. Assessments included the Clinician-Administered PTSD Scale, Clinical Global Impressions of Change, Treatment Outcome PTSD Scale, Davidson Trauma Scale, Connor-Davidson Resilience Scale, Sheehan Disability Scale, Massachusetts General Hospital Sexual Functioning Questionnaire, and Montgomery-Asberg Depression Rating Scale. A total of 232 patients (tiagabine, n = 116; placebo, n = 116) were randomized. There were no significant differences in change from baseline in the Clinician-Administered PTSD Scale total score at final visit for tiagabine compared with placebo (P = 0.85). Similarly, no significant differences were observed with tiagabine on the other efficacy outcome measures (described above) compared with placebo. Tiagabine was generally well tolerated and not associated with weight gain, changes in sexual function, or worsening of depressive symptoms. Tiagabine was not significantly different from placebo in the treatment of symptoms of PTSD. Additional studies are needed to assess the role of drugs that target the gamma-aminobutyric acid system in the treatment of PTSD.