Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy of adults and the second responsible cause of cancer-related death around the world. Hepatocellular carcinoma (HCC) accounts for about 90% of primary liver malignancies. In Egypt chronic hepatitis C virus (HCV) is a major health burden and a major risk factor for HCC. Alteration of DNA Methylation at promoter regions has a recognized role during early evolution and development of human diseases, including cancers. It can be in the form of hypermethylation, hypomethylation, and loss of imprinting. RUNX3 and P16 are tumor suppressor genes that may be inactivated by hypermethylation which is a key epigenetic mechanism that contributes to the initiation and progression of various types of human carcinomas including HCC. To the extent of our knowledge, there are few studies regarding the association of hypermethylation of RUNX3 and p16 gene promoters with the incidence of HCC. This review highlights the relationship of the (CpG) Island methylator phenotype with RUNX3 Gene and P16 Gene methylation and HCC prognosis in Egyptian patients.