OBJECTIVES: Rifaximin is a minimally absorbed antimicrobial agent that has demonstrated efficacy for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in 3 multicenter, randomized, controlled trials. After an initial 2-week course of therapy, rifaximin should be considered for repeat treatment only upon recurrence of symptoms, in contrast to other IBS treatment options that require chronic administration to maintain symptom improvement. The aim of this study was to evaluate the cost of adopting rifaximin for treating patients with IBS-D. METHODS:  A model was created to project the incremental budget impact of adding rifaximin for treating patients with IBS-D in the US. The budget impact (2014 dollars) with rifaximin was estimated based on a hypothetical health plan with 10,000,000 members and 138,813 treated IBS patients receiving antidiarrheals, rifaximin, antispasmodics, alosetron, lubiprostone, linaclotide, and tricyclic antidepressants. Drug acquisition and office visit costs were applied to estimate the budget impact relative to the current environment over 3 years. Uptake of rifaximin was assumed to be 3.5% (year 1), 8.5% (year 2), and 15% (year 3). Adverse events and their associated costs were deemed similar between treatments and not included. RESULTS: The projected 1-, 2-, and 3-year budget impact of rifaximin resulted in annual savings for the health plan of $4,673,829 [per member per month (PMPM): $0.04], $11,350,728 (PMPM: $0.09), and $20,030,696 (PMPM: $0.17), totaling $36,055,253 over 3 years. Model results were most sensitive to time horizon, unit drug costs, and annual doses of alosetron and rifaximin; however, these only impacted the magnitude of savings relative to the current environment. Savings were expected when rifaximin was administered for up to 2 courses of therapy annually. CONCLUSIONS: This model suggests that the treatment of IBS-D with rifaximin, despite its higher unit cost, may be associated with savings when used up to twice per year.