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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.