摘要Objective: We aimed to directly compare the estimated effects of adherence to a healthy lifestyle with those of risk predisposition according to known genetic variants affecting colorectal cancer (CRC) risk, to support effective risk communication for cancer prevention. Methods: A healthy lifestyle score (HLS) was derived from 5 lifestyle factors: smoking, alcohol consumption, diet, physical activity, and body adiposity. The association of lifestyle and polygenic risk score (PRS) (based on 140 CRC-associated risk loci) with CRC risk was assessed with multiple logistic regression and compared through the genetic risk equivalent (GRE), a novel approach providing an estimate of the effects of adherence to a healthy lifestyle in terms of percentile differences in PRS. Results: A higher HLS was associated with lower CRC risk (4,844 cases, 3,964 controls). Those adhering to all 5 healthy lifestyle factors had a 62％ (95％ CI 54％–68％) lower CRC risk than those adhering to ≤ 2 healthy lifestyle factors. The estimated effect of adherence to all 5 compared with ≤ 2 healthy lifestyle factors was as strong as the effect of having a 79 percentile (GRE 79, 95％ CI 61–97) lower PRS. The association between a healthy lifestyle and CRC risk was independent of PRS level but was particularly pronounced among those with a family history of CRC in ≥ 1 first-degree relative (P-interaction = 0.0013). Conclusions: A healthy lifestyle was strongly inversely associated with CRC risk. The large GRE indicated that CRC risk determined by polygenic risk may be offset to a substantial extent by adherence to a healthy lifestyle.