Some patients with irritable bowel syndrome (IBS) show poor response to treatment. However, risk factors associated with poor therapeutic response have not been determined. This multicenter trial evaluated consecutive outpatients with IBS undergoing treatment for more than 1 month. Mental health status and physical function were evaluated using the Japanese version of the SF-8. Therapeutic response was evaluated using the IBS severity index-Japanese version (IBS-SIJ). Patients with IBS-SIJ scores175 were defined as poor responders to treatment, whereas those with IBS-SIJ scores < 175 were defined as good responders. The demographic and clinical characteristics of these two groups, along with medications, were compared. The study enrolled 131 participants, 75 with IBS-SIJ scores175-56 with IBS-SIJ scores < 175. Multiple logistic regression analysis showed that female sex [odds ratio (OR) 2.67, 95 % confidence interval (CI) 1.19-5.97, p = 0.0167] and mental component summary (MCS) of the SF-8 < 40 (OR 2.58, 95 % CI 1.12-5.97, p = 0.0263) were independent risk factors for poor therapeutic response in patients with IBS. Lower MCS and female sex were risk factors for poor therapeutic response in patients with IBS. Ascertaining the mechanisms by which lower MCS and female sex are associated with poor therapeutic response in IBS may help design better treatments (Trial registration number: UMIN000016804).