Here, leveraging a large IBD exome sequencing dataset comprising 38,558 cases and 66,945 controls of European ancestry in the discovery stage and a combined total of 42,475 cases and 192,050 controls across diverse ancestry groups in the replication stage, we established a protective role of CF-risk variants against IBD based on the association test of CFTR deltaF508 (p = 8.96E-11) and the gene-based burden test of CF-risk variants (p = 3.9E-07). This evidence concerns the gene CFTR and inflammatory bowel disease.