Objective: To investigate the relationship of microRNA499 (miR-499) gene polymorphism with genetic susceptibility of hepatocellular carcinoma (HCC) and its predictive value on prognosis. Methods: 80 patients with HCC were selected as experimental group, and 30 patients who were admitted to the hospital for physical examination during the same period were regarded as control group. Venous blood samples were collected to obtain the gene distribution status of miR-499 rs3746444 locus, and the relationship between different genotypes and HCC genetic susceptibility was analyzed. The clinical information and follow-up status of experimental group were combined to explore the influence of miR-499 gene polymorphism on the prognosis of patients with HCC. Results: Carrying miR-499 C/C genotype and allele C could increase the genetic susceptibility of HCC by 2.399 times and 2.282 times (P<0.05). The overall survival rate of patients with miR-499 C/C genotype was lower than that of patients with C/T and T/T genotypes (P<0.05). High alpha-fetoprotein, low degree of differentiation and miR-499 C/C genotype were all independent risk factors of poor prognosis in patients with HCC (P<0.05). Conclusion: The C/C genotype of miR-499 gene is a susceptible genotype of HCC and an independent risk factor of poor prognosis.