Currently, there is no standard treatment for posttraumatic stress disorder (PTSD) because of a deficit of systematic treatment trials. The symptom overlap with other mood and anxiety disorders that respond to antidepressants and the results of a limited number of antidepressant trials indicate promise for psychopharmacologic treatment. Several open trials and one controlled trial with selective serotonin reuptake inhibitors have reported improvement in the symptomatology of PTSD. In this study, a relatively new serotonergic antidepressant, nefazodone, was tested as a treatment for PTSD. Veterans with chronic PTSD (N = 36) were enrolled in an 8-week open-label trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Thirty-one patients completed at least 4 weeks of treatment, which was considered to be an adequate trial, and 26 patients completed the 8-week study. During treatment, there was a significant decrease in the total CAPS score and in each of three CAPS subscale scores, with most of the improvement occurring during the first 4 weeks. Comparable improvements were also seen on the Hamilton Rating Scales for Anxiety and for Depression. Nefazodone treatment was well tolerated by this patient population, with only four patients discontinuing because of adverse effects. In summary, nefazodone treatment improved the symptoms of PTSD, including the core symptoms. Placebo-controlled studies should be undertaken to further elucidate the efficacy of nefazodone in the treatment of PTSD.