MicroRNAs (miRNAs) play an important role in the pathogenesis of neoplasm. Single nucleotide polymorphisms (SNPs) within miRNAs can change their phenotype and function. We attempted to analyze the relationship between two SNP loci in miRNAs and colorectal cancer (CRC) in Chinese Han population. We genotyped the polymorphism of two common miRNA SNPs, miR-146a (rs2910164 G > C) and miR-499 (rs3746444 T > C), in a case-control study of 276 CRC cases and 373 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The genotypes and allele frequencies of the two SNP loci were first compared between patients and controls and then further analyzed among subgroups of patients with different clinicopathological profiles. The rs2910164 CG genotype was significantly associated with a decreased risk of CRC [CG versus GG, odds ratio (OR) = 0.567; 95% confidence intervals (CIs) = 0.338-0.952; p = 0.031]. No significant differences of miR-499 genotype and allele distribution were detected between patients and controls. Comparison between groups divided by clinicopathologic features showed that the polymorphism of miR-146a was associated with the degree of tumor differentiation (p = 0.014), and the G allele of rs2910164 trended to a mature differentiation (OR = 0.553; 95% CI = 0.315-0.971; p = 0.038). MiR-146a (rs2910164 G > C) polymorphism is associated with CRC susceptibility and histological differentiation in Chinese Han population.