We explored the association between 4 XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) polymorphisms with the development and prognosis of hepatocellular carcinoma (HCC). A total of 218 cases with HCC and 277 healthy controls were included in the study. Genotyping of the XRCC1 (Arg194Trp and Arg399Gln) and XPD (Asp312Asn and Lys751Gln) polymorphisms was performed in a 384-well plate format on the Sequenom MassARRAY platform. We found that individuals with the XRCC1 399AA genotype had a higher risk of HCC compared with the GG genotype (odds ratio, OR = 1.85, 95% confidence interval, CI = 1.03-3.23). Similarly, individuals carrying the XPD 751GG genotype showed a greatly increased risk of HCC (OR = 2.97, 95%CI = 126- 7.38). Cox regression analysis showed that individuals carrying XPD 751Gln/Gln genotypes had a 0.30-fold increased risk of death from HCC. These results suggest that polymorphisms in XRCC1 and XPD may have functional significance in HCC.