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Background Both lifestyle factors and genetic predisposition contribute to the development of diverticulitis.Objective To examine whether lifestyle modification can reduce the genetic risk of diverticulitis.Design We derived an overall healthy lifestyle score for diverticulitis based on smoking, body mass index (BMI), physical activity, fibre and red meat among 179 564 participants in three prospective cohorts-the Nurses’ Health Study (NHS), NHSII and the Health Professionals Follow-Up Study. The association between the healthy lifestyle score and incident diverticulitis was confirmed among 30 750 participants in the Southern Community Cohort Study (SCCS). We assessed genetic risk using a polygenic risk score among 36 077 individuals with genotype data available. We further validated our findings in the Mass General Brigham Biobank (MGBB).Results A healthy lifestyle score was associated with a decreased risk of diverticulitis. Compared with a score of 0, the multivariable-adjusted HR for a score of 5 was 0.50 (95% CI, 0.44 to 0.57; p trend<0.0001). This association was consistent across the SCCS in both non-Hispanic black and white populations. Each unit increase in the healthy lifestyle score was associated with a reduced diverticulitis risk similarly across genetic risk categories, with HRs of 0.89 (95% CI, 0.83 to 0.95) for low, 0.86 (0.81 to 0.92) for mid and 0.87 (0.83 to 0.91) for high genetic risk. In the MGBB cohort, a higher BMI was associated with an increased diverticulitis risk across genetic risk categories.Conclusion Maintaining a healthy lifestyle was associated with a reduced risk of developing diverticulitis, regardless of population differences and genetic susceptibilities.