Background Hepatocellular carcinoma (HCC) is one of the life-threatening malignancies worldwide with hepatitis B and C virus infection as the major risk factor. The risk of HCC might also increase because of the hereditary genetic defects in DNA repair genes. In this regard, X-ray cross-complementing group 1 gene (XRCC1) is a major DNA repair gene involved in base excision repair (BER). Aim The present study was designed with an aim to find out any possible association between XRCC1 (codons 194, 280, and 399) polymorphisms and the risk of developing hepatitis virus-related HCC in Indian population. Methods A total of 407 subjects comprising (170 controls, 174 chronic viral hepatitis, and 63 HCC subjects) were included in the study. PCR-RFLP was used for the genotyping of the three codons of XRCC1. Results The study revealed that two genotypes Arg194Trp and Arg280His increased the risk of HCC by 2.27- (95% CI = 1.01-5.08; P < 0.001) and 4.95-folds (95% CI = 2.48-9.89; P < 0.001), respectively. Interestingly, the risk for HCC was further enhanced by 35.96 (95% CI = 11.64-110.91; P < 0.001) and 5.28 times (95% CI = 2.81-9.09; P < 0.001) when the genotype Arg280His was found in association with Arg194Trp and Arg399Gln, respectively. Conclusion These preliminary results suggest a positive association of XRCC1 genotypes and risk of hepatitis virus-related HCC in India.