Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. The aim of the present study was to assess the association of mutation of specific genes: cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), microsomal epoxide hydrolase (EPHX) and paraoxonase (PON1) and environmental exposures on the risk of HCC in Egypt. A case-control study was conducted on 459 subjects with confirmed HCC recruited from the National Cancer Institute, Cairo University, Egypt, and 634 controls recruited from orthopedic department, Cairo University Hospital, Egypt and from two villages in Menoufiya governorate. Patients who agreed to participate signed a consent form, answered a questionnaire and gave a blood sample for hepatitis virus and genetic testing. PON1 polymorphism was inversely related to HCC, OR was 0.7 (95% CI: 0.5-1.1). EPHX1 Slow activity was significantly associated with HCC (OR= 1.5, 95% CI: 1.1-2.2) compared to high metabolizers after adjustment with age, sex, current HCV and current HBV infection. CYP1A1 mutation was not associated with HCC in the present study (OR= 2.0, 95% CI: 0.4-10.2). CYP2D6 extensive metabolizers was associated with HCC (OR= 1.8, 95% CI: 1.1-3.0) compared to poor metabolizers. No significant interaction between smoking or pesticides exposure and the studied genes. As expected, the strongest risk factors for HCC in this study were HCV RNA (OR = 11-13) and current HBV infection (OR = 6-9). This study therefore suggests that mutation in the studies genes are additive risk factors to current HCV and HBV infection.