Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, the prevalence and mortality rates of which are very high in Taiwan. The study aimed at evaluating the contribution of XRCC7 G6721T, together with cigarette smoking and alcohol drinking lifestyles, to the risk of HCC. In this hospital-based case-control study, the association of XRCC7 single nucleotide polymorphism G6721T with HCC risk was examined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) among 298 HCC patients and 889 age- and gender-matched healthy controls. The results showed that the percentages of TT, GT, and GG XRCC7 G6721T were 53.0, 41.3, and 5.7 % in the HCC patient group and 48.9, 43.1, and 8.0 % in the non-cancer control group, respectively. We have further stratified the populations by genders, cigarette smoking, and alcohol drinking status to investigate their combinative contributions with XRCC7 G6721T genotype to HCC risk. The results showed that the GG genotype of XRCC7 G6721T conducted a protective effect on HCC susceptibility which was obvious among males and drinkers, but not females, smokers, non-smokers, or non-drinkers (p = 0.0058, 0.0069, 0.1564, 0.2469, 0.9354, and 0.3416, respectively). Our results suggested that the GG and GT genotypes of X-ray repair cross-complementing group 7 (XRCC7) G6721T had no effect on HCC risk to the whole population, but had a protective effect on HCC risk among males and alcohol drinkers.