This study will evaluate the effectiveness and safety of repeat treatment with rifaximin 550 mg three times a day in patients with IBS with diarrhea who respond to initial treatment of rifaximin 550 mg three times a day.

It is important in chronic conditions to have information about how a product that is intended for short course administration in order to confer prolonged benefit should be administered beyond the first cycle of use once symptoms reappear. This Phase 3 study will evaluate the efficacy and safety of repeat treatment with rifaximin 550 mg three times daily (TID) for 14 days in subjects with IBS-D who respond to an initial treatment course with rifaximin 550 mg TID for 14 days.

This study consists of several treatment phases outlined below:

Screening/Treatment 1 Phase. Subjects will receive single-blind placebo TID for 7-13 days and answer daily IBS symptom-related questions.

Treatment 2 Phase. Eligible subjects will receive open-label rifaximin 550 mg TID for 2 weeks with a 4-week treatment-free follow-up. Responders will continue into Maintenance Phase 1. Nonresponders will withdraw from the study.

Maintenance Phase 1. Subjects will continue the treatment-free follow-up period for up to 18 weeks until either: 1) they experience recurrence or 2) enrollment is met in the Treatment 3 Phase (Double Blind Repeat Treatment Phase). Subjects who do not meet recurrence criteria by the end of the Maintenance Phase 1 will withdraw from the study.

Treatment 3 Phase/ Double Blind Repeat Treatment Phase. Subjects who meet criteria for recurrence will be randomized 1:1 to receive either rifaximin 550 mg TID or placebo TID for 2 weeks with a 4-week treatment-free follow-up.

Primary efficacy analysis will be performed at the end of the Treatment 3 Phase (at Week 6 of the double-blind period).

Maintenance Phase 2. All subjects continued into an additional treatment-free follow-up period of up to 6 weeks (Maintenance Phase 2).

Treatment 4 Phase/Second Repeat Treatment Phase. Subjects will receive the same double-blind treatment as previously assigned in the Treatment 3 Phase for 2 weeks with a 4-week treatment-free follow-up.

A lactulose breath test sub-study will be conducted at select sites.

Inclusion Criteria:

• IBS confirmed by Rome III diagnostic criteria.
• At least 18 years of age.
• Colonoscopy within the past 10 years to rule out inflammatory bowel disease; or flexible sigmoidoscopy if < 50 years of age or previous colonoscopy > 10 years prior.
• Willing to maintain a stable diet. including vitamins, supplements, and nutraceuticals.

Exclusion Criteria:

• Diabetes (Type 1 or 2).
• Lactose intolerance and not controlled by a lactose-free diet.
• Pregnant or planning to become pregnant or is lactating.
• History of HIV or hepatitis B or C.
• Participation in investigational study within past 30 days.
• Taking rifaximin or any other antibiotic within past 60 days.
• Unstable cardiovascular or pulmonary disease, with change in treatment in last 30 days due to worsening disease condition.
• History of GI surgery.