BACKGROUND: Lifestyle modifications play an important role in the management of irritable bowel syndrome (IBS), but there is limited information on any associations of combined lifestyle-related factors with IBS in Middle Eastern populations. We, therefore, assessed the associations of a "lifestyle score," in analogy to lifestyle scores applied in studies of other disorders, with IBS in adults. METHODS: In a cross-sectional study on 3363 Iranian adults, a healthy lifestyle score (HLS) was constructed using information about dietary habits, dietary intake, physical activity, smoking status, and psychological distress, which was collected using validated questionnaires. A modified version of the Rome III questionnaire (in Persian) was used to diagnose IBS and its subtypes. KEY RESULTS: Individuals with the highest HLS had a 65% lower odds of having IBS compared with those in the lowest category (OR: 0.35; 95% CI: 0.26-0.48). Participants with healthy dietary habits, including regular meal pattern, slow/moderate eating rate, moderate intra-meal fluid consumption, moderate/long meal-to-sleep interval, and low/moderate consumption of fatty foods, had significantly lower odds of having IBS compared with those with unhealthy dietary habits (OR: 0.81; 95% CI: 0.69-0.96). Moreover, individuals with lower levels of psychological distress, compared with those with higher levels of distress, had significantly lower odds of IBS (OR: 0.49; 95% CI: 0.40-0.60). CONCLUSIONS AND INFERENCES: Our data suggest that having an overall "healthy lifestyle" is related to substantially reduced odds of IBS, suggesting that adhering to a healthy lifestyle pattern, including dietary habits, diet quality, physical activity, smoking, and psychological distress, can be considered as a key management strategy for IBS.