OBJECTIVE: Diarrhea and small intestinal bacterial overgrowth (SIBO) are key features in certain patients with irritable bowel syndrome (IBS). Rifaximin and Medilac-S are commonly used agents to treat IBS. This study aimed to observe the clinical effects of rifaximin and Medilac-S in diarrhea-predominant IBS (IBS-D) with SIBO. STUDY DESIGN: In total, 136 IBS-D patients with SIBO were divided into 3 groups to receive Medilac-S (probiotic group), rifaximin (rifaximin group) or Medilac-S combined with rifaximin (combined group), respectively. Changes in the symptoms, which included severity and frequency of abdominal pain, frequency of defecation, and fecal characteristics, were recorded and scored. Blood samples were collected to measure serum interleukin–6 (IL-6), tumor necrosis factor–alpha (TNF-α), intestinal mucosal barrier-associated factor D–lactic acid (D-LA), and bacterial endotoxin lipopolysaccharide (LPS) using the enzyme-linked immunosorbent assay technique. RESULTS: There were statistically significant differences in the scores for abdominal pain severity, abdominal pain frequency, defecation frequency, total symptoms, IL-6, TNF-α, D-LA, and LPS before and after treatment between the 3 groups (p<0.05 or p<0.01). After treatment there were statistically significant differences in abdominal pain severity score, abdominal pain frequency score, TNF-α, and LPS between the combined and probiotic groups (p<0.05 or p<0.01); in abdominal pain severity score between the combined and rifaximin groups (p<0.05); and in TNF-α and LPS between the rifaximin and probiotic groups (p< 0.05 or p<0.01). There were also statistically significant differences in SIBO-negative conversion rate and significantly effective rate among the 3 groups after treatment, and the combined group showed better outcomes than the probiotic group (p<0.05). CONCLUSION: Overall, this study indicated that the treatment of IBS-D with SIBO with rifaximin and Medilac-S was highly effective in clinical settings. © Science Printers and Publishers, Inc.