This study aimed to examine whether theISXrs5755368 genotypes are associated with the effect of dietary retinol consumption on CRC risk. We recruited 923 CRC patients and 1846 controls to identify the association between dietary retinol and CRC risk. Dietary retinol intake was assessed using a semiquantitative food frequency questionnaire. Genotype data were available for 1419 patients (600 cases and 819 controls) of the total study population. Genotyping was performed using an Illumina MEGA Expanded Array. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression models. Retinol intake was inversely associated with CRC (OR = 0.49; 95% CI = 0.37–0.63). Participants with AA genotype showed lower CRC risk than subjects carrying the G allele (AG + GG) (OR = 0.76; 95% CI = 0.58–0.99). A 68% reduced risk of CRC was related to subjects who had the highest retinol intake and carrying AA genotype compared to the risk of participants consumed the lowest retinol intake and carrying the G allele (OR = 0.32; 95% CI = 0.20–0.53;Pinteraction = 0.026). Retinol intake could be a protective factor for CRC risk while this association could be strengthened among individuals carrying the homozygous AA genotype.