Background: Chronic hepatitis C virus (HCV) infection is the most frequent cause of progressive liver disease and hepatocellular carcinoma (HCC) in Egypt. Risk of HCC can be affected by the exposure to endogenous or environmental toxins. Genetic polymorphism of the carcinogens-metabolizing enzymes, were suggested as modifiers of cancer risk. So, the present study aimed to investigate the association between xenobiotic metabolizing enzymes [cytochrome P450 (CYP2D6), N-acetyl transferase 2 (NAT2) and UDP-glucuronosyltransferase 1A7 (UGT1A7)] gene polymorphism and the risk of HCC in patients with chronic HCV-induced cirrhosis compared to normal and chronic HCV infected subjects. Subjects and Methods: 354 subjects, divided into 3 groups, (group I: 150 patients had chronic hepatitis C with HCC, group II: 104 patients had chronic hepatitis C without HCC and group III: 100 healthy controls. The studied genes were genotyped using polymerase chain reaction-restriction fragment length polymorphism and allelic discrimination assays. Results: CYP2D6*6 and CYP2D6*3 poor metabolizers (homozygous mutant genotypes) were significantly increased in HCC patients compared to controls and were associated with increased HCC risk with ORs and 95%CI of 4.0 (2.5-6.4) and 3.32 (2.1-5.2) respectively. Meanwhile, CYP2D 6*4 extensive metabolizer (homozygous wild genotypes; GG) was significantly increased in HCC patients compared to controls and was associated with increased HCC risk with ORs and 95%CI of 2.3 (1.42-3.85). However homozygous mutant genotypes (slow acetylators) of NAT2 M1, M2 and M3 showed no significant difference between HCC patients and controls and were not associated with increased HCC risk. Also, genotypes of UGT1A7 gene showed no significant difference in HCC patients compared to other groups and had no effect on HCC susceptibility. Conclusion: Poor metabolizers' genotypes of CYP2D 6*6 and CYP2D 6*3 and extensive metabolizer genotypes of CYP2D 6*4 may be risk factors for HCC in patients infected with HCV. Meanwhile, NAT2 and UGT1A7 genes polymorphism were not associated with increased risk of HCC in the studied patients.