Abstract: Background and Objective: The liver is the main metabolic organ, carcinogen-metabolizing liver enzymes are the most important candidates that may influence hepatocarcinogenesis associated with heavy metal overload. This study was aimed at analyzing the genetic pattern regarding the proto-oncogene (L-myc) and the cytochrome (CYP2E1), which are involved in detoxification and oncogenesis, in both HCC patients and controls and to study the likelihood of each genetic pattern to develop HCC in the presence of heavy metals load. Materials and Methods: Total 171 hepatocellular carcinoma patients were included and 143 matched healthy controls in this study. Routine laboratory tests and heavy metals (lead, cadmium, arsenic and mercury) concentration were measured. Genetic polymorphisms was detected by a PCR-RFLP method. Student’s t-test and SPSS software used for statistical analysis. Results: C2 allele and C2 containing genotypes of CYP2E1 showed a significant higher percentage in HCC group (p = <0.001). Distribution of different L-myc genotypes in HCC and control groups showed nonsignificant difference ( p = 0.140). As regards the heavy metals concentration in carriers of different genotypes of both CYP2E1 and L-myc revealed no significant difference except for mercury which reported higher levels with the mutant homozygote genotype of L-myc (p = 0.015). Conclusion: There was no significant association between gene polymorphisms and heavy metal burden within HCC patients. It is also noted that CYP2E1 polymorphisms may increase HCC susceptibility while L-myc gene polymorphism showed non significant difference between HCC patients group and control group.