Objective To investigate the effects of mutations at coding regions of X-ray repair complementing group 4 (XRCC4) and xeroderma pigmentosum group C (XPC) on the development and prognosis of hepatocellular carcinoma (HCC) related to aflatoxin B1(AFB1) exposure. Methods This study, including 1 499 HCC cases of HCC and 2 049 controls, was a hospital-based case-control study. TaqMan-PCR technique was employed to test genotypes of XRCC4 codon 247 and XPC codon 939, whereas logistic regression model and Cox's regression model were used to analyse the correlation of XRCC4 and XPC mutations with development and prognosis of AFB1-related HCC. Results The mutations at coding regions of XRCC4 and XPC gene increased the risk of development of HCC, with relative odd ratios of 2.01 and 1.76 for XRCC4 and XPC respectively (P<0.05). The mutative genotypes of XRCC4 and XPC genes interacted with AFB1 exposure in development of HCC. Furthermore, the mutative genotypes of these two genes modified the prognosis of HCC. Conclusion The mutations at coding regions of XRCC4 and XPC may increase the risk of development of AFB1-related HCC and modulate the prognosis of HCC.