Posttraumatic stress disorder (PTSD) is a prevalent condition that has been shown to be responsive to pharmacotherapy. Few head-to-head comparisons of medications used in the treatment of PTSD have been published. This 12-week, randomized, double-blind study compares the effectiveness, safety, and tolerability of nefazodone and sertraline for the treatment of PTSD. Thirty-seven male and female outpatients meeting DSM-IV criteria for PTSD were randomly assigned to receive nefazodone (maximum dose 600 mg/day; average dose 463 mg/day) or sertraline (maximum dose 200/day; average dose 153 mg/day). The primary outcome measures were the 17-item total severity score of the Clinician Administered PTSD Scale, Part 2 (CAPS-2) and the Clinical Global Impression Improvement Scale (CGI-I). Other assessments included the Davidson Trauma Scale (DTS), the Top-8 PTSD Rating Scale, Sheehan Disability Scale (SDS), Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAM-A), and Pittsburgh Sleep Quality Index (PSQI). Twenty-six subjects had at least one post-randomization CAPS-2 assessment and were therefore included in the data analysis. There were no statistically significant differences between treatment groups on any of the outcome measures. There was a significant effect for time in both groups, indicating an improvement in PTSD symptoms, depression, sleep, and quality of life over time. CAPS-2 scores for all of the PTSD symptom clusters decreased significantly over time. This study did not find significant differences in the effectiveness of nefazodone and sertraline for the treatment of PTSD. Larger trials are warranted.