The aim of this study is to examine the empirical insulinemic potential consisting of dietary and lifestyle factors and the interactive effect with the common genetic susceptibility locus rs2423279 on the risk of CRC. This case-control study was conducted with 923 CRC patients and 1,846 controls. The empirical measures for assessing the insulinemic potential, namely, the empirical dietary index for hyperinsulinemia (EDIH), for insulin resistance (EDIR), the empirical lifestyle index for hyperinsulinemia (ELIH), and for insulin resistance (ELIR), were calculated based on semiquantitative food frequency and lifestyle questionnaires. A genetic variant of rs2423279 was genotyped. The CRC patients were more likely to score in the highest quartile for the ELIH (OR Q4 vs Q1, 95% CI = 2.90, 2.01 - 4.19, P for trend < 0.001), EDIR (OR Q4 vs Q1, 95% CI = 3.32, 2.32 - 4.74, P < 0.001), and ELIR (OR Q4 vs Q1, 95% CI = 2.79, 1.96 - 3.97, P < 0.001) than were the controls. The significant effect between the ELIR, which assesses dietary and lifestyle patterns related to insulin resistance, and C allele carriers of rs2423279 was stronger than that for homozygous T allele carriers (OR, 95% CI = 2.50, 1.78 - 3.51, P for interaction = 0.034). The empirical insulinemic potential for insulin resistance might have interactive effects with the rs2423279 polymorphism on the risk of CRC. The results of this study suggest the basis of the metabolic impact of the insulin response on colorectal carcinogenesis.