ObjectiveTo estimate the proportion of cases of Crohn’s disease (CD) and ulcerative colitis (UC) that could be prevented by modifiable lifestyle factors.DesignIn a prospective cohort study of US adults from the Nurses’ Health Study (NHS; n=72 290), NHSII (n=93 909) and Health Professionals Follow-up Study (HPFS; n=41 871), we created modifiable risk scores (MRS; 0–6) for CD and UC based on established lifestyle risk factors, and healthy lifestyle scores (HLS; 0–9) derived from American healthy lifestyle recommendations. We calculated the population attributable risk by comparing the incidence of CD and UC between low-risk (CD-MRS≤1, UC-MRS≤2, HLS≥7) and high-risk groups. We externally validated our findings in three European cohorts: the Swedish Mammography Cohort (n=37 275), Cohort of Swedish Men (n=40 810) and European Prospective Investigation into Cancer and Nutrition (n=404 144).ResultsOver 5 117 021 person-years of follow-up (NHS, HPFS: 1986–2016; NHSII: 1991–2017), we documented 346 CD and 456 UC cases. Adherence to a low MRS could have prevented 42.9% (95% CI 12.2% to 66.1%) of CD and 44.4% (95% CI 9.0% to 69.8%) of UC cases. Similarly, adherence to a healthy lifestyle could have prevented 61.1% (95% CI 16.8% to 84.9%) of CD and 42.2% (95% CI 1.7% to 70.9%) of UC cases. In our validation cohorts, adherence to a low MRS and healthy lifestyle could have, respectively, prevented 43.9%–51.2% and 48.8%–60.4% of CD cases and 20.6%–27.8% and 46.8%–56.3% of UC cases.ConclusionsAcross six US and European cohorts, a substantial burden of inflammatory bowel diseases risk may be preventable through lifestyle modification.