BACKGROUND: Alterations in gut flora may be important in the pathophysiology of the irritable bowel syndrome (IBS). OBJECTIVE: To determine whether the nonabsorbed antibiotic rifaximin is more effective than placebo in reducing symptoms in adults with IBS. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: 2 tertiary care medical centers. PARTICIPANTS: 87 patients who met Rome I criteria for IBS and were enrolled from December 2003 to March 2005. Interventions: Participants who met enrollment criteria were randomly assigned to receive 400 mg of rifaximin 3 times daily for 10 days (n = 43) or placebo (n = 44). Eighty participants completed rifaximin therapy or placebo, and follow-up data were available for at least 34 participants per study group at any time point thereafter. MEASUREMENTS: A questionnaire was administered before treatment and 7 days after treatment. The primary outcome was global improvement in IBS. Patients were then asked to keep a weekly symptom diary for 10 weeks. RESULTS: Over the 10 weeks of follow-up, rifaximin resulted in greater improvement in IBS symptoms (P = 0.020). In addition, rifaximin recipients had a lower bloating score after treatment. LIMITATIONS: The major limitations of the study were its modest sample size and short duration and that most patients were from 1 center. CONCLUSIONS: Rifaximin improves IBS symptoms for up to 10 weeks after the discontinuation of therapy.