This study was performed to investigate the effect of PD-L1 polymorphisms on the susceptibility and prognosis of hepatocellular carcinoma (HCC) in a Chinese Han population.Four single nucleotide polymorphisms (SNPs) of the PD-L1 gene, including rs2297136 (C > T), rs4143815 (C > G), rs2890658 (A > C) and rs17718883 (C > G) were examined in 225 HCC patients and 200 healthy controls using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method.Data revealed that the rs2297136 (C > T) SNP TT (p = 0.03) and rs4143815 (C > G) SNP GG genotypes (p < 0.001) were associated with significantly increased risks of HCC. No association was found between rs2890658 (A > C) SNP and HCC risk and this risk was significantly decreased in individuals with the rs17718883 SNP CG + GG genotype (p < 0.001). The rs2297136 (C > T) SNP CC + CT genotypes, the rs4143815 (C > G) CC genotype and the rs2890658 (A > C) AA genotype were associated with increased overall survival compared to their counterpart allelic genotypes (p < 0.001). The rs2890658 (A > C) SNP had no impact on the risk and prognosis of HCC (p > 0.05).Our results indicated that three functional polymorphisms (rs2297136, rs4143815 and rs17718883) of the PD-L1 gene were associated with HCC risk and prognosis, suggesting that genetic variants of PD-L1 polymorphisms might be a possible prognostic marker for the prediction of HCC risk and development. Validation by a larger prospective study from a more diverse ethnic population is needed to confirm these findings.