Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract that causes abdominal pain or discomfort and alters bowel with no organic abnormalities. Treatment options for IBS have increased in number in the past decade, and clinicians should not be limited to use only conventional treatments to cure it. This article is a placebo-controlled clinical trial to assess the therapeutic effects of low-dose bismuth subcitrate on symptoms and the health-related quality of life in adult patients with IBS. Methods: This clinical trial was done during July 2015 to January 2016 in Isfahan, Iran. For each of three subtypes (IBS-constipation dominant, IBS-diarrhea dominant [IBS-D], and IBS-mixed), we included patients with IBS aged 18–70 years, diagnosed according to the Rome III criteria. In this study, 129 eligible patients were enrolled, of which 119 continued on the protocol to the end of study. They were allocated in placebo group (Group A) and intervention group (Group B). The medication for Group B was mebeverine and bismuth subcitrate and for Group A was mebeverine and placebo of bismuth subcitrate. Initially, the patients of both groups completed IBS-related questionnaires (IBS-quality of life, IBS-severity scoring system), then given drugs for a 4-week period (1^st on-drug period). Then, both groups were given only mebeverine hydrochloride 200 mg capsule for another 4 weeks (off-drug period). At last, Group A and Group B were given medication (2^nd on-drug period), the same as 1^st on-drug period. Findings: With respect to quality of life, the trend of IBS-QOL score changed significantly during the study period in both the intervention and placebo groups; however, no significant differences were observed between the two groups (P < 0.005). In subgroups analysis, quality of life significantly improved in IBS-D during the study from the first measurement to the end of study (P = 0.004). The trends of changes in the severity of pain during the study between the intervention and control group were significantly different (P = 0.018). Conclusion: According to our study, IBS-D patients' symptoms improved significantly with bismuth therapy. We found that adding low-dose bismuth to mebeverine in nonresponsive IBS patients in conventional treatment could be helpful.