To evaluate the efficacy of sertraline in the treatment of posttraumatic stress disorder (PTSD) in a Veterans Affairs (VA) clinic setting involving patients with predominantly combat-related PTSD. 169 outpatient subjects with a DSM-III-R diagnosis of PTSD and who scored 50 or higher on Part 2 of the Clinician-Administered PTSD Scale (CAPS-2) at the end of a 1-week placebo run-in period participated. Patients recruited from 10 VA medical centers were randomly assigned to 12 weeks of flexibly dosed sertraline (25-200 mg/day) (N = 86; 70% with combat-related PTSD; 79% male) or placebo (N = 83; 72% combat-related PTSD; 81% male) between May 1994 and September 1996. The primary efficacy measures were the mean change in CAPS-2 total severity score from baseline to endpoint, in the total score from the Impact of Event Scale, and in the Clinical Global Impressions-Severity of Illness and Improvement scales. There were no significant differences between sertraline and placebo on any of the primary or secondary efficacy measures at endpoint. In order to understand the results, gender, duration of illness, severity of illness, type of trauma, and history of alcohol/substance abuse were explored as potential moderators of outcome, but no consistent effects were uncovered. Sertraline was well tolerated, with 13% of patients discontinuing due to adverse events. Sertraline was not demonstrated to be efficacious in the treatment of PTSD in the VA clinic settings studied.