Background Category Ⅲ chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common syndrome of unclear etiology with significant impact on quality of life. Because the outcomes of multiple therapies for CP/CPPS have been far from approving, the possible psychological factors have been considered to play an important role in CP/CPPS.Based on this, we investigated the role of antidepressant drug (fluoxetine) in men with refractory CP/CPPS.Methods In this study, 42 men diagnosed with refractory CP/CPPS without response to standard therapy (include multiple antibiotic courses and a-blockers) were referred for fluoxetine therapy. All patients received fluoxetine (20 mg/d) for three months and were clinically evaluated before (baseline), and after 4, 8 and 12 weeks of therapy. The evaluation included a National Institutes of Health-chronic prostatitis symptom index (NIH-CPSI) and a Beck depression inventory (BDI) questionnaire. Moreover, the subjective global assessment (SGA) was assessed at the 4th, 8th and 12th week of therapy.Results Significant decreases were observed for total NIH-CPSI (28.55 to 9.29), NIH-CPSI pain (14.69 to 5.19),NIH-CPSI urinary (4.95 to 1.88 ), NIH-CPSI quality of life (8.83 to 2.20), and BDI (34.67 to 13.95) scores compared with baseline, all P values ＜0.05. Twenty-nine (69.05%) reported marked improvement on the subjective global assessment and 33 (78.57%) had a greater than 50% decrease in NIH-CPSI at the end of therapy (12th week). At the same time, the Pearson correlation coefficient analysis demonstrated a positive correlation between BDI score and each CPSI score. No adverse events were reported in this study.Conclusions Fluoxetine appears to be a safe and effective treatment in improving symptoms in, and the quality of life of, men with difficult CP/CPPS. Moreover, amelioration of difficult CP/CPPS-related symptoms could be related to a decrease in depressive symptoms.