INTRODUCTION: To investigate the prospective association of irritable bowel syndrome (IBS) with long-term risk of overall, site-specific cancer and cancer-specific mortality in general population. METHODS: Participants free of inflammatory bowel disease, celiac disease, and any cancer at baseline from the UK Biobank were included, with patients with IBS as the exposure group and non-IBS patients as the reference group. The primary outcome was the incidence of overall cancer and cancer-specific mortality. Secondary outcomes included site-specific cancers and types of digestive cancers. The Cox proportional hazard model was used to investigate the associated risk of incident malignancies and related mortality. RESULTS: Among 449,595 participants, 22,338 (5.0%) were diagnosed with IBS. During a median of 12.2-year follow-up, 2,937 cases of incident cancer were identified in patients with IBS (11.47 per 1,000 person-years), compared with 60,556 cases in reference individuals (12.51 per 1,000 person-years). Of these cases, 512 and 12,282 cancer-specific deaths occurred in IBS and non-IBS groups. Compared with non-IBS, the adjusted hazard ratio for overall cancer and cancer-specific mortality was 0.97 (95% confidence interval: 0.93-1.00, P = 0.062) and 0.83 (0.76-0.91, P < 0.001) among patients with IBS. Specifically, decreased risk of digestive (0.79 [0.71-0.89]), particularly colon (0.75 [0.62-0.90]) and rectal (0.68 [0.49-0.93]), cancers was observed in patients with IBS. Further sensitivity analysis and subgroup analysis by age and sex indicated similar results. DISCUSSION: Compared with the general population, IBS does not increase the overall risk of cancer. Conversely, IBS is associated with lower risk of incident colorectal cancer and cancer-specific mortality.