X-ray repair complementing group 4 (XRCC4) is very important in maintaining overall genome stability and may play an important role in carcinogenesis. We aimed to investigate the role of polymorphisms in the coding region of this gene in hepatocellular carcinoma (HCC) caused by aflatoxin B1 (AFB1). A hospital-based case-control study, including 1,499 HCC cases and 2,045 controls without any liver diseases or tumors, was conducted in a high AFB1 exposure area (the Guangxi region) to assess the relationship between 21 polymorphisms in the coding region of XRCC4 and AFB1-related HCC risk and prognosis. Among these 21 polymorphisms, only rs28383151 modified HCC risk. These individuals with the genotypes of rs28383151 A alleles (rs28383151-GA/AA), compared with the homozygote of rs28383151 G alleles (rs28383151-GG), faced increasing risk of HCC (odds ratio [OR]: 2.17; 95% confidence interval: 1.77-2.67). Significant interactive effects between risk genotypes (OR, >1) and AFB1 exposure status were also observed in the joint-effects analysis. Furthermore, this polymorphism was correlated not only with lower XRCC4-expressing levels, but also with higher AFB1-DNA adducts levels and increasing TP53M and portal vein tumor risk. The rs28383151 polymorphism modified the recurrence-free survival and overall survival of HCC patients, especially under high AFB1 exposure conditions. Additionally, this polymorphism multiplicatively interacted with the glutathione S-transferase M1 polymorphism with respect to HCC risk (ORinteraction = 2.13). Conclusion: Genetic polymorphisms in the coding region of XRCC4 may be risk and prognostic biomarkers of AFB1-related HCC, and rs28383151 is such a potential candidate. (HEPATOLOGY 2013) © 147.