background: Although plenty of medications have shown promise in the treatment of irritable bowel syndrome (IBS), none have relieved all complaints adequately to be considered as gold standard. Based on previous data. regarding the effectiveness of olanzapine in other functional or psychosomatic disorders and clinical experience of the authors on its efficacy and safety, we considered to test this drug in combination with citalopram for IBS.Materials and Methods: IBS patients who were refractory to conventional treatments were assigned randomly to take placebo or citalopram (C) with either placebo or olanzapine (0) by which, 38, 36 and 38 patients entered in the study in each group, respectively. The patients were evaluated for quality of life (IBS-QOL), severity and frequency of symptoms, depression and anxiety (HADS) before intervention and 4 and 12 weeks after initiation of the treatment. Thirty one of the placebo (P) group versus 13 patients of the control (C+P) and 17 of the case (C+O) completed the full course of study.Results: While there was a trend toward better results in intervention groups compared to placebo alone, no statistically significant difference was observed among the three intervention groups in quality of life (p=0.799), but, there was a significant improvement from pretest scores in both 4 and 12 week observations in all three groups (p<0.001). Similar findings were detected between the two intervention groups for severity and frequency of symptoms as well as anxiety and depression scores. There was a significant rate of discontinuation of the study in the intervention groups compared to the placebo group.Conclusion: citalopram neither alone nor in combination with olanzapine added significant benefits to IBS symptoms in this study.