BACKGROUND The efficacy of the nonabsorbable antibiotic rifaximin in patients with active acute or chronic pouchitis is unknown. METHODS We performed a placebo-controlled pilot trial to evaluate the efficacy and safety of rifaximin in patients with active pouchitis. Eighteen patients with active pouchitis were randomized to receive oral rifaximin 400 mg or placebo 3 times daily for 4 weeks. Active pouchitis was defined as a total Pouchitis Disease Activity Index (PDAI) score = 7 points. Clinical remission was defined as a PDAI score <7 points and a decrease in the baseline PDAI score = 3 points. The primary analysis was clinical remission at week 4. RESULTS Eight patients were randomized to rifaximin and 10 patients were randomized to placebo. One patient in the placebo group did not have a post-baseline efficacy evaluation and was excluded from the efficacy analysis. Two of 8 patients (25%) treated with rifaximin were in clinical remission at week 4 compared to 0 of 9 patients (0%) treated with placebo (P = 0.2059). None of 8 patients in the rifaximin group withdrew from the trial prior to week 4. Two of 9 patients in the placebo group withdrew prior to week 4 due to lack of efficacy and were categorized as treatment failures. CONCLUSIONS Clinical remission occurred more frequently in patients treated with rifaximin 400 mg 3 times daily but the difference was not significant in this pilot study. A larger trial would be required to determine if rifaximin is effective for the treatment of active pouchitis. Rifaximin was well tolerated.