Numerous reports have explored the roles of different genetic variants in miRNA biogenesis mechanisms and the progression of various types of carcinomas. The goal of this study is to explore the association betweenXPO5*rs34324334andRAN*rs14035gene variants and susceptibility to hepatocellular carcinoma (HCC). In a cohort of 234 participants (107 HCC patients and 127 unrelated cancer-free controls) from the same geographic region, we characterized allelic discrimination using PCR-RFLP and performed subgroup analysis and multivariate regression. We found that the frequency of theXPO5*rs34324334(A) variant was correlated with elevated risk of HCC under allelic (OR = 10.09,p-value < 0.001), recessive (OR = 24.1,p-value < 0.001), and dominant (OR = 10.1,p-value < 0.001) models. A/A genotype was associated with hepatitis C cirrhosis (p-value = 0.012), ascites (p-value = 0.003), and higher levels of alpha-fetoproteins (p-value = 0.011). Carriers of the RAN*rs14035 (T) variant were more likely to develop HCC under allelic (OR = 1.76,p-value = 0.003) and recessive (OR = 3.27,p-value < 0.001) models. Our results suggest thatXPO5*rs34324334andRAN*rs14035variants are independent risk factors for developing HCC.