AbstractBackgroundBoth inflammatory bowel disease (IBD) and hepato‐pancreato‐biliary cancers (HPBC) have been established to cause a huge socioeconomic burden. Epidemiological studies have revealed a close association between IBD and HPBC.MethodsHerein, we utilized inverse‐variance weighting to conduct a two‐sample Mendelian randomization analysis. We sought to investigate the link between various subtypes of IBD and HPBC. To ensure the accuracy and consistency of our findings, we conducted heterogeneity tests, gene pleiotropy tests, and sensitivity analyses.ResultsCompared to the general population, IBD patients in Europe exhibited a 1.22‐fold increased incidence of pancreatic cancer (PC) with a 95% confidence interval (CI) of 1.0022–1.4888 (p= 0.0475). We also found a 1.14‐fold increased incidence of PC in Crohn's disease (CD) patients with (95% CI: 1.0017–1.3073,p= 0.0472). In the East Asian population, the incidence of hepatocellular carcinoma (HCC) was 1.28‐fold higher (95% CI = 1.0709–1.5244,p= 0.0065) in IBD patients than in the general population. Additionally, ulcerative colitis (UC) patients displayed 1.12‐fold (95% CI: 1.1466–1.3334,p< 0.0001) and 1.31‐fold (95% CI: 1.0983–1.5641,p= 0.0027) increased incidences of HCC and cholangiocarcinoma (CCA), respectively. Finally, the incidence of PC was 1.19‐fold higher in CD patients than in the general population (95% CI = 1.0741–1.3132,p= 0.0008).ConclusionOur study validated that IBD is a risk factor for HPBC. This causal relationship exhibited significant heterogeneity in different European and East Asian populations.