INTRODUCTION: This pilot study determined the efficacy of rifaximin, a gut-directed antibiotic, in reducing chronic prostatitis (CP) and gastrointestinal (GI) symptoms in patients with CP type III. The prevalence of small intestinal bacterial overgrowth (SIBO) and irritable bowel syndrome (IBS) in patients with CP was also evaluated. MATERIALS AND METHODS: Chronic prostatitis patients were recruited and screened for SIBO and IBS using the lactulose breath test (LBT) and Rome II criteria, respectively. Patients with a positive LBT result and Chronic Prostatitis Symptom Index (CPSI) score = 15 received rifaximin 550 mg three times daily for 10 days. The CPSI score and global improvement of CP and GI symptoms were ascertained at screening (ie, 7 days before therapy), at baseline immediately before therapy (ie, day 0), and on days 14 and 28. Results: Fourteen of 16 CP patients (88%) had a positive LBT result and were included in this therapeutic study (mean age, 41 years). Mean CPSI score significantly decreased from screening to day 28 (ie, 18 days after rifaximin treatment; p = 0.043). Mean abdominal pain and bloating scores were also significantly reduced on day 28 versus baseline (p = 0.010 and p = 0.003, respectively). Chronic prostatitis patients with IBS and SIBO had a statistically significant response as well. RESULTS: Data from this pilot study suggest that SIBO and IBS are common in CP and that patients with CP and SIBO may benefit from rifaximin therapy. Further studies are warranted.