We studied polymorphisms of three genes, UDP-glucuronosyltransferase1A7 (UGT1A7), Glutathione-S-transferaseM1 (GSTM1) and X-Ray Cross Complementing group 1 (XRCC1), involved in detoxification of xenobiotics or DNA-repair in a population of 133 liver-transplanted patients, including 56 patients with hepatocellular carcinoma (HCC) and 77 without HCC, and in 89 healthy controls originating from the south of France. Multiple logistic regression analysis showed that, among liver-transplanted patients, interactions between XRCC1-G/G or -G/A and GSTM1-nul polymorphisms were independently associated with hepatocellular carcinoma (p interaction=0.027) concurrently with increasing age (p<0.001), male sex (p=0.037) and chronic hepatitis B or C virus infection (p=0.018 and p=0.001 respectively). On the contrary, no relationship was observed between UGT1A7 polymorphisms considered alone or in interaction with GSTM1 or XRCC1 polymorphisms and HCC. This suggests that concomitant impaired metabolism of carcinogenic compounds and impaired DNA-repair function play an important role in liver carcinogenesis in high-risk cirrhotic patients originating from the south of France.