Multiyear (37-51 months) follow-up data was obtained on patients who had participated in an open label trial of nefazodone that originally showed nefazodone may be useful for symptom management in posttraumatic stress disorder (PTSD) patients. Ten patients with combat-related DSM-IV posttraumatic stress disorder (PTSD) entered an open-label 12-week trial of nefazodone, beginning with 100 mg/day and increasing as necessary to achieve a maximal response or until reaching a maximum dosage of 600 mg/day. All 10 patients were followed for over 3-4 years and used nefazodone with dosages of 400-600 mg a day. The entire dosagewas shifted to bedtime to facilitate sleep in 7 patients. Data on PTSD symptoms, depression, sleep, and anger were examined. Nefazodone was well tolerated and no significant changes in sexual function were reported. All participants reported compliance with the prescribed nefazodone over 3-4 years. Nine patients reported that it remained effective, and expressed a desire to remain on the medication. On the basis of clinician global impression ratings (compared to baseline), 10 patients were rated as much improved at 12 weeks. Seven of the 10 patients continued to be much improved, 2 were minimally improved, and 1 was rated as worse (compared to baseline assessment) on 3-4-year follow-up. At 3-4-year follow-up, improvements in PTSD symptoms, sleep, and anger were maintained. These improvements were statistically significant with moderate-to-large effect sizes. These data suggest that clinical improvement in PTSD patients administered nefazodone may be maintained with continued treatment. The medication was tolerated well in long-term treatment, compliance was high, and improvement was maintained over several years. Length of treatment, appropriate dose, long-term efficacy, and compliance are all clinically significant issues with little guiding data available. Controlled studies are needed to (a) further investigate the long-term efficacy of nefazodone in the treatment of PTSD; (b) provide information for length of treatment guidelines; and (c) document if discontinuation is possible and efficacious.