Objective: To explore the relationship of XRCC1 Arg 399 Gln polymorphism and AFB1-related hepatocellular carcinoma (HCC) risk in Guangxi population. Methods: The DNA samples from peripheral blood white blood cells were obtained from subjects including 140 HCC and 536 controls. The XRCC1 gene 399 codon polymorphism was detected by PCR-RFLP technique. Results: The frequency of XRCC1 399 Arg/Gln & Gln/Gln genotype in HCC patients (48.57%) was significantly higher that in normal controls (32.46%), and XRCC1 399 Arg/Gln & Gln/Gln genotype was associated with increased risk of HCC (adjusted odds ratios (OR)=2.18, 95% confidence interval (CI) 1.27~3.74). In addition, in the cohort of low/median level of AFB1 exposure, the codon 399 Gln allele was associated with a conspicuous significantly increasing risk for HCC (adjusted OR=2.06, 95% CI=1.01~4.20). Conclusion: The results indicate that the XRCC1 399 Gln allele is a potentially important determinant of susceptibility to AFB1-related HCC.