Background & Aims: Psychological treatment and the efficacy of drug therapy are considered to be useful in quality of life and symptoms of patients with irritable bowel syndrome. The aim of this study was to examine the effects of cognitive-behavior therapy associated with drug therapy in comparison to drug therapy alone on the quality of life and symptoms of IBS patients with diarrhea predominance. Method: This study was a randomized clinical trial on 64 IBS patients. The patients were selected according to Rome-III criteria, and were divided into the two groups. Bowel Symptoms Severity and Frequency Scale (BSS-FS) and Quality Of Life (QOL-IBS) were used for evaluation of patients’ symptoms. The first group underwent cognitive-behavior therapy with medication therapy, and the second group only received medication. Data were analyzed using analysis of multiple covariances (MANCOVA). Results: The two groups showed significant difference in the QOL-IBS in post treatment 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 study period (P < 0.05). However, no significant difference was observed at followup stage between the two groups (P > 0.05). Conclusion: Cognitive-behavior therapy associated with drug therapy can be useful in IBS patients with diarrhea predominance. However, stopping this treatment may lead to recurrence of the symptoms.