AIM: To comparatively evaluate the long term efficacy of Rifaximin and dietary fibers in reducing symptoms and/or complication frequency in symptomatic, uncomplicated diverticular disease.METHODS: 307 patients (118 males, 189 females,age range: 40-80 years) were enrolled in the study and randomly assigned to: Rifaximin (400 mg bid for 7 d every month) plus dietary fiber supplementation (at least 20 gr/d) or dietary fiber supplementation alone.The study duration was 24 mo; both clinical examination and symptoms' questionnaire were performed every two months.RESULTS: Both treatments reduced symptom frequency,but Rifaximin at a greater extent, when compared to basal values. Symptomatic score declined during both treatments, but a greater reduction was evident in the Rifaximin group (6.4 + 2.8 and 6.2 + 2.6 at enrollment,P = NS, 1.0 + 0.7 and 2.4 + 1.7 after 24 mo, P ＜ 0.001,respectively). Probability of symptom reduction was higher and complication frequency lower (Kaplan-Meyer method) in the Rifaximin group (P ＜ 0.0001 and 0.028,respectively).CONCLUSION: In patients with symptomatic,uncomplicated diverticular disease, cyclic administration of Rifaximin plus dietary fiber supplementation is more effective in reducing both symptom and complication frequency than simple dietary fiber supplementation.Long term administration of the poorly absorbed antibiotic Rifaximin is safe and well tolerated by the patients,confirming the usefulness of this therapeutic strategy in the overall management of diverticular disease.