Objective: To evaluate the association of gene polymorphisms of the SNP of TNF-α gene -238G>A and IL-18 gene-607C>A with the development of hepatocellular carcinoma among Egyptian patients. Methods: One hundred and fifty patients were allocated to this study; eighty patients with hepatocellular carcinoma (Group A), seventy cancer-free HCV age, and sex-matched patients (Group B). We analyzed two Single nucleotide polymorphisms (SNPs) (TNF-α-238G>A and IL-18-607C>A) by real-time polymerase chain reaction using sequence-specific primers (PCR-SSP). Results: Significant higher risk of HCC was associated with genotype IL-18-607AA (P<0.001), OR: 5(2.188-11.47), allele IL-18 -607⁄A (P=0.001), OR: 2.1(1.32-3.3). A significant association was found between the size of HFL in the HCC group and different genotypes of IL18 genes (P=0.013) where 62.5% of patients with tumor size >5 cm carried the risky (AA) genotype on the other hand the SNP of TNF-α gene -238G>A showed no statistically significant association between the two groups. Conclusion: The SNP -607C>A in the IL18 gene was associated with increased HCC risk in Egyptian patients suggesting its use as a potential diagnostic non-invasive tool that allows to identify a new group of HCC patients at an earlier stage.