MicroRNAs (miRNAs) can contribute to the development of cardiovascular diseases, and single nucleotide polymorphisms (SNPs) in miRNA genes may influence disease susceptibility by altering mature miRNA expression levels. However, the effect of SNPs located in miR-146a and miR-196a2 genes on risk of acute coronary syndrome (ACS) has not been reported in the Chinese population. Two miRNA polymorphisms located in miRNA genes (miR-146a rs2910164 C>G and miR-196a2 rs11614913 T>C) were genotyped in 722 ACS patients and 721 control subjects. The CG genotype of rs2910164 was significantly associated with decreased risk of ACS [CG vs. CC, odds ratio (OR) = 0.72, 95% confidence interval (CI): 0.55-0.95, P = 0.020; dominant model, OR = 0.77, 95% CI: 0.60-0.99, P = 0.044]. We did not find any association of rs11614913 with the risk of ACS. Stratification analysis showed that the rs2910164 CG genotype was associated with decreased risk of ACS (dominant model) in males, subjects with body mass index more than 24 kg/m(2), and in hypertensive subjects. Significant combined effects were also observed between rs2910164 and blood lipids or C-reactive protein levels. In summary, this study provides the first evidence that the CG genotype of miR-146a rs2910164 is associated with a significantly decreased risk of ACS in a Chinese population. Moreover, rs2910164 and blood lipids or an inflammatory marker may have a combined effect on the onset of ACS. These findings indicate that miR-146a rs2910164 may act as a novel molecular marker for ACS susceptibility.