BACKGROUND: Accumulated studies have suggested that single nucleotide polymorphisms (SNPs) in microRNAs are associated with risk of colorectal cancer (CRC). OBJECTIVE: We tested our hypothesis that rs11014002 in hsa-miR-603 may be associated with CRC risk with a crosstalk of life-related factors. METHODS: We conducted a case-control study which included 102 CRC patients and 204 matched cancer-free controls in Xiaoshan County. RESULTS: We observed that subjects with rs11014002 CT/TT genotype had an increased susceptibility for CRC (CT vs. CC: odds ratio (OR) = 2.352, 95% confidence interval (CI): 1.142-4.840, P = 0.020; CT+TT vs. CC: OR = 2.031, 95% CI: 1.063-3.883, P = 0.032). After stratification by lifestyle-related factors, similar results were found among nonsmokers (CT vs. CC: OR = 2.753, 95% CI: 1.085-6.983, P = 0.033; CT+TT vs. CC: OR = 2.971, 95% CI: 1.188-7.435, P = 0.020) and non-alcohol drinkers (CT+TT vs. CC: OR = 3.279, 95% CI: 1.071-10.033, P = 0.037). CONCLUSIONS: Our data suggest that hsa-miR-603 may be involved in colorectal tumorigenesis, and the genetic polymorphism in hsa-miR-603 is associated with CRC susceptibility.