It is unclear whether dietary lutein/zeaxanthin intake in colorectal cancer is associated with microRNA processing involved in DICER1 cleavage for messenger RNA translation. We investigated whether dietary lutein/zeaxanthin intake affects colorectal cancer risk in patients with a DICER1 rs3742330 polymorphism. In this hospital-based case-control study, we recruited 923 colorectal cancer patients and 1,846 controls based on eligibility criteria, a semiquantitative food frequency questionnaire and the DICER1 rs3742330 genotype. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression adjusted for confounders. The highest quartile of lutein/zeaxanthin consumption was inversely associated with a reduced colorectal cancer risk (OR, 95% CI = 0.25, 0.18-0.36). Carrying G allele (AG + GG) showed a significantly reduced colorectal cancer incidence compared with that of AA carriers (OR, 95% CI = 0.71, 0.55-0.91). Those carrying the G allele (AG + GG) along with high lutein/zeaxanthin consumption were markedly associated with a decreased colorectal cancer risk (OR, 95% CI = 0.32, 0.22-0.46, P for interaction = 0.018), particularly for rectal cancer (OR, 95% CI = 0.24, 0.15-0.39, P for interaction = 0.004), compared with that of AA carriers with low lutein/zeaxanthin intakes. In conclusion, colorectal cancer risk was related to an interactive effect between dietary lutein/zeaxanthin intake and the DICER1 rs3742330 polymorphism.