BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder which its treatment is still a question. According to the literature, the use of antidepressants is common for IBS, while its efficacy in this regard is controversial. This study has been raised to assess the efficacy of venlafaxine in IBS patients. MATERIALS AND METHODS: In this double-blind, randomized clinical trial, 33 patients with moderate-to-severe IBS were included and randomly divided into two groups by using permuted block randomization process of size 4 for each block to receive Venlafaxine or placebo. Venlafaxine in 37.5 mg/day for 2 weeks, followed by 75 mg/day for the next 2 weeks and then 150 mg/day until the end of the study was prescribed. Gastrointestinal symptoms severity, depression, anxiety, stress as main, and quality of life (QoL) as the secondary outcomes were evaluated at the study initiation, within 2, 6, and 12 weeks after treatment and 3 months after intervention cessation. RESULTS: The gastrointestinal symptoms severity, depression, anxiety, stress, and QoL scores significantly improved in patients who received Venlafaxine but not in placebo group; although after treatment discontinuation they experienced relapse ( < 0.05). Patients treated with venlafaxine experienced significant improvement in IBS symptoms, all three psychological disorders and QoL than placebo group ( < 0.01). The frequency of observed side effects in venlafaxine group including vomiting, nausea, and sleep disturbance was higher than placebo. CONCLUSION: Venlafaxine could be considered as an effective treatment for improving gastrointestinal symptoms severity, depression, anxiety, stress, and QoL of patients with IBS. Further studies with larger sample size and longer treatment duration are recommended.