BACKGROUND: The relationship between non-alcoholic fatty liver degree as well as non-alcoholic fatty liver disease (NAFLD) and irritable bowel syndrome (IBS) remains poorly understood. We aimed to investigate the prospective association of non-alcoholic fatty liver degree as well as NAFLD with incident IBS in a large-scale population-based cohort. METHODS: Participants free of IBS, coeliac disease, inflammatory bowel disease, alcoholic liver disease, and any cancer at baseline from the UK Biobank were included. Non-alcoholic fatty liver degree was measured by a well-validated fatty liver index (FLI), with FLI ≥ 60 as an indicator of NAFLD. Primary outcome was incident IBS. Cox proportional hazard model was used to investigate the associated risk of incident IBS. RESULTS: Among 396,838 participants (mean FLI was 48.29 ± 30.07), 153,203(38.6%) were with NAFLD diagnosis at baseline. During a median of 12.4-year follow-up, 7129 cases of incident IBS were identified. Compared with non-NAFLD, NAFLD patients showed a 13% higher risk of developing IBS (HR = 1.13, 95%CI: 1.05-1.17) after multivariable adjustment. Compared with the lowest, the highest FLI quartile was associated with a significantly increased risk of IBS (HRQ4 VS Q1 = 1.21, 1.13-1.30, Ptrend < 0.001). Specifically, the positive association between non-alcoholic fatty liver degree and IBS was also observed by per SD change of FLI (adjusted HR = 1.08, 1.05-1.10). Further sensitivity analysis and subgroup analysis indicated similar results, with the positive association particularly observed in females, but not in males. CONCLUSIONS: High degree of non-alcoholic fatty liver as well as non-alcoholic fatty liver disease is associated with increased risk of incident IBS. Further studies are warranted to confirm the findings and elucidate the underlying biological mechanisms.