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INTRODUCTION: The impact of lifestyle changes after colorectal cancer (CRC) screening on risk of CRC and major chronic diseases remains unknown.METHODS: Leveraging the repeatedly collected dietary, lifestyle, and screening data in the Nurses' Health Study (1988-2018), Nurses' Health Study II (1993-2019) and Health Professionals Follow-up Study (1988-2016), we assessed changes after initial colonoscopy screening in a healthy lifestyle score (0-5) based on smoking, body mass index, physical activity, alcohol intake, and diet. We used time-varying multivariable Cox regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence of CRC and major chronic diseases (including cancer, cardiovascular disease, and type 2 diabetes), among 118,396 and 88,558 individuals, respectively.RESULTS: During a median follow-up of 10.0 years (interquartile range 6.2-12.6) and 9.6 years (interquartile range 6.0-12.3 years), we documented 537 CRC and 14,165 major chronic disease cases, respectively. Forty-eight percent of participants changed their lifestyle score with at least 1 point. One-unit increase in the lifestyle score was associated with 14% lower risk of CRC (HR 0.86, 95% CI 0.77-0.95) and 11% lower risk of major chronic diseases (HR 0.89, 95% CI 0.88-0.91). Similar associations were observed for proximal and distal CRC and individual chronic diseases. Changes in smoking and physical activity were associated with CRC and chronic diseases, whereas changes in weight, alcohol intake, and diet were associated with chronic diseases only.DISCUSSION: Adopting a healthier lifestyle after initial colonoscopy screening may reduce risk of CRC and chronic diseases, suggesting colonoscopy screening could be a teachable moment for health promotion.