Nefazodone is a unique serotonergic antidepressant that acts as both a presynaptic serotonin reuptake inhibitor and a postsynaptic 5-hydroxytryptamine 2A receptor antagonist. Based on the positive results of open-label trials of nefazodone, including one from our group, we tested nefazodone's efficacy in the treatment of posttraumatic stress disorder (PTSD) under placebo-controlled conditions. Forty-one patients with chronic PTSD, predominantly male combat veterans, were enrolled in a randomized, double-blind, placebo-controlled 12-week trial of nefazodone. The primary outcome measure was the Clinician-Administered PTSD Scale. Fifteen patients were randomized to placebo and 26 were randomized to nefazodone. In a repeated-measures analysis of variance with last observation carried forward, patients on nefazodone showed a significant improvement in the percentage change of Clinician-Administered PTSD Scale Total score from baseline compared with those on placebo (P = 0.04; effect size = 0.6). Sample size was not powered to test group differences in the Clinician-Administered PTSD Scale criterion B, C, or D subscale. However, the criterion D subscale showed significant improvement in patients treated with nefazodone compared with those treated with placebo (P = 0.007). In addition, the Hamilton Rating Scale for Depression showed significant improvement compared with placebo (P = 0.008). The nefazodone group also reported an improvement on the PTSD Checklist (self-report scale; P = 0.08) and the Clinician-Administered Dissociative States Scale (P = 0.06). This pilot study supports the efficacy of nefazodone for the treatment of PTSD. However, larger placebo-controlled studies in more diverse patient population are warranted.