Several studies reported the association between the miR-146a rs2910164 polymorphism and Hepatocellular Carcinoma (HCC) risk, but the results were controversial. Thus, we did a case-control study to determine the association between miR-146a rs2910164 polymorphism and HCC risk. This study included 188 HCC cases and 186 controls. HCC was diagnosed by liver biopsy. Healthy individuals undergoing routine medical examination without any medical illness. CG genotype in HCC patients with miR-146a rs2910164 polymorphism increased the risk of HCC (OR=1.99, 95% CI 1.27-3.11, P=0.003). CC genotype in HCC patients with miR-146a rs2910164 polymorphism also showed an increased risk of HCC (OR=3.30, 95% CI 1.72-6.32, P=0.0003). In addition, patients with CG and CC had significant increased risk of HCC (OR=2.24, 95% CI 1.47-3.42, P=0.0002) in dominant model. Further, patients with CC genotype also had increased risk of HCC (OR=2.29, 95% CI 1.25-4.19, P=0.0002) in recessive model. The C allele seemed to be a risk factor of HCC (OR=1.88, 95% CI 1.39-2.54, P<0.0001). In conclusion, the study suggested that miR-146a rs2910164 polymorphism was significantly associated with HCC risk.