Psychotherapy and drug therapy are considered useful in quality of life (QOL) and symptoms of patients with irritable bowel syndrome (IBS). The aim of this study was to examine the effects of cognitive behavioral therapy (CBT) associated with drug therapy in comparison to drug therapy alone on the QOL and symptoms of IBS patients with diarrhea predominance. This study was a randomized clinical trial on 64 IBS patients. The patients were selected according to Rome III criteria and were assigned into two groups. Bowel symptom severity and frequency scale and QOL-IBS were used to investigate the patients' symptoms. The first group underwent CBT with medication therapy, and the second group received only medication. Data were analyzed using analysis of multiple covariance. The two groups showed a significant difference in the QOL-IBS in posttreatment and follow-up stages (P < 0.05). There were significant differences in the severity and frequency of IBS symptoms between the two groups after the intervention (P0.05). CBT accompanied by drug therapy can be useful for IBS patients with diarrhea predominance. However, discontinuing this treatment may lead to recurrence of the symptoms.