Hepatocellular carcinoma (HCC) is a life-threatening disease that is often associated with chronic infection by hepatitis B and C viruses. Genetic polymorphisms have been reported to alter the risk for HCC development. Genetic studies based on the haplotype have an increased power for detecting disease associations compared with single-nucleotide polymorphism-based analysis. There is sufficient epidemiological evidence suggesting a link between genetic polymorphism and haplotypes of microsomal epoxide hydrolase (mEPHX) and X-ray cross-complementing group 1 (XRCC1) with altered cancer risk. However, no report correlates the risk of HCC development with mEPHX and XRCC1 haplotypes. Genetic polymorphism of these genes was studied for haplotype construction in 169 control subjects, 174 hepatitis patients, and 63 HCC patients. 113Tyr-139Arg and 113His-139His haplotypes of mEPHX significantly elevated the risk for HCC by 1.4- and 1.5-folds, respectively. Arg-His-Arg haplotype of XRCC1 significantly enhanced the risk for hepatitis by 2.8-folds (p = 0.001), but not for HCC (odds ratio = 1.5; p = 0.28). mEPHX haplotypes shared a positive association with HCC risk in India.