Purpose: The nonsystemic antibiotic rifaximin is indicated for the treatment of diarrhea-predominant IBS (IBS-D) in adults. In order to gain a better understanding of the safety profile of rifaximin for the management of this condition, a pooled analysis was conducted to evaluate the overall safety and tolerability profile of rifaximin in IBS-D. Methodology: A post hoc pooled analysis included data from a phase 2b study (rifaximin 275 mg, 550 mg, or 1100 mg or placebo twice daily for 2 weeks), phase 3 TARGET 1 and 2 (rifaximin 550 mg or placebo 3 times daily for 2 weeks) studies, and the double-blind retreatment phase of phase 3 TARGET 3 (2 courses of rifaximin 550 mg or placebo 3 times daily for 2 weeks, separated by a 6-week treatment-free follow-up phase). Safety was assessed through 12 weeks posttreatment (phase 2b), 10 weeks posttreatment (TARGET 1 and 2), and through 4 weeks posttreatment after receiving the second retreatment course (TARGET 3). Population included all patients with ≥1 dose of double-blind study medication and ≥1 postbaseline safety assessment. Results: The analysis included 2568 patients (n = 1431 rifaximin, n = 1137 placebo). A treatment-emergent adverse event (AE) was experienced by 50.2% and 50.7% of patients in the rifaximin and placebo groups, respectively. The majority of AEs were mild to moderate in intensity; severe AEs were reported by 4.6% in the rifaximin group and 5.8% in the placebo group. Drug-related AEs were reported in 9.8% and 8.5% of patients in the rifaximin and placebo groups, respectively. The most common AEs (≥2% of patients in rifaximin group) occurring with rifaximin versus placebo were headache (4.4% vs 5.3%), upper respiratory tract infection (4.3% vs 4.8%), nausea (4.2% vs 3.3%), urinary tract infection (3.4% vs 2.9%), abdominal pain (3.1% vs 3.6%), diarrhea (3.1% vs 2.6%), nasopharyngitis (2.5% vs 4.2%), and sinusitis (2.2% vs 2.6%). Constipation was reported in 0.9% of the rifaximin group and 1.6% of the placebo group. Serious AEs were experienced by 1.4% (rifaximin) and 1.9% (placebo) of patients; 1 event in the rifaximin group (alcohol withdrawal syndrome) was considered related to study drug. One patient developed Clostridium difficile during the TARGET 3 treatment-free observation phase. The patient had a history of C difficile and received a 10-day course of cefdinir for a urinary tract infection; this AE was nondrug–related. AEs resulted in study discontinuation in 1.6% of patients in the rif...