The aim of this study is to investigate the associations between EZH2 gene polymorphisms and colorectal cancer (CRC) risk. We undertook a case-control study to analyze three EZH2 polymorphisms (148505302C>T, 2110+6A>C and 626-394T>C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 512 patients with CRC and 546 control participants, and performed EZH2 genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in 2,110+6A>C. Nevertheless, 148505302C>T genotype demonstrated a protective effect in CRCs (P=0.014; odds ratio (OR) 0.777, CI 95%:0.647-0.933). Furthermore, 148505302 T allele CRC was more significantly common in patients with tumor size of <4 cm than C allele CRC and in cases of good differentiation and lower advanced pathological stage. However, 626-394T>C genotype was at increased risk of CRCs (P<0.001; odds ratio (OR) 1.457, CI 95%:1.160-1.829). Moreover, 626-394C/C genotype CRCs were more significantly common in patients with tumor size of >4 cm than T allele CRC and in cases of poor differentiation and lower advanced pathological stage. In conclusion, polymorphism in 626-394T>C was observed to be associated with susceptibility of CRC. However, 148505302C>T polymorphism indicated to play a protective role in susceptibility to CRC. Nevertheless, further investigation with a larger sample size is needed to support our results.