BACKGROUND: Psychological distress and perceived stress may complicate the clinical presentation, course, and treatment of patients with functional gastrointestinal disorders. The correlation between psychological distress, perceived stress, and the nocebo effect (multifood adverse reaction) in patients with irritable bowel syndrome (IBS) was the main aim of the present study. MATERIALS AND METHODS: In this cross-sectional correlation study, data on 4,763 Iranian adults, 748 of whom by purposive sampling were patients with IBS (65.1% female), working in 50 different health centers affiliated to the Isfahan University of Medical Sciences across Isfahan province were examined. For assessing dietary intake, a 106-item self-administered Dish-based Semi-Quantitative Food Frequency Questionnaire that was specifically designed and validated for Iranian adults was used. General Heath Questionnaire 12 and Stressful Life event Questionnaire were used to assess psychological distress and perceived stress. By using a modified Persian version of the Rome III questionnaire, IBS was assessed. Based on researcher-made definition of nocebo effect (multiitem food intolerance), 164 people had the nocebo phenomenon in IBS group. RESULTS: Age, sex, education, marital status, antidepressant use, and specifically chronic underlying disease (odds ratio [OR]: 3.54, 95% confidence interval [CI]: 1.73-7.23) of general characteristics had a significant correlation ( <.05) with presenting nocebo responses in IBS patients. Psychological distress (OR: 1.415; 95% CI: 0.992-2.020; = 0.056) had a significant correlation with nocebo effect and did not find significant correlation with perceived stress (OR: 0.999; 95% CI: 0.990-1.008; = 0.865). Data were analyzed by Chi-square test, analysis of variance, and OR. CONCLUSION: The present study showed that psychological distress with chronic underlying disease and antidepressant use are important elements in presenting multifood adverse reactions that we named here as the nocebo effect in IBS patients. Reducing psychological distress and managing chronic underlying diseases appear to be an effective factor in reducing the nocebo phenomenon in IBS patients. For managing the nocebo responses in IBS patients, these findings may help clinicians to improve their interventions. Further studies are required to confirm these findings.