We read with interest the article by Lembo et al1 evaluating the safety and efficacy of repeat treatment with rifaximin in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). The authors found that repeat rifaximin treatment was efficacious and well-tolerated in a phase III study of patients with relapsing symptoms of IBS-D. Because their findings are important to both current practice and future research, several questions deserve attention.