Background: Aberrant promoter methylation of several tumor suppressor genes (TSGs) and tumor-related genes is a frequent observation that increases during the progression from precancerous lesion to HCC. Thus, epigenetic changes in preneoplastic or early stages may serve as “biomarker” for screening and early detection of HCC.Aim Of The Work: this study was designed to assess the frequency of methylation of TSGs (P14, P15 &P73) and the DNA mismatch repair gene (O6MGMT) in patients within the whole spectrum of HCV related CLD (chronic hepatitis, liver cirrhosis and HCC) to assess the ability to be used for early prediction of HCC.Methods: Plasma samples were obtained from 200 HCC patients, 108 HCV-related liver cirrhosis and 100 chronic HCV patients in addition to 100 HBV & HCV seronegative controls. Routine clinical, laboratory and ultrasonographic assessments were done. HCC was diagnosed according to AASLD guidelines. Methylation frequency was assessed by DNA methylation specific PCR.Results: promoter methylation of P14, P15 and P73 genes was detected with different frequencies in the whole spectrum of HCV related CLD including HCC and also in control group but with no significant difference between the studied groups. O6MGMT gene promoter methylation was the only marker that showed significant difference between the studied groups. Concluson: promoter gene methylation was evident in HCV related CLD and HCC. O6MGMT could be a possible epigenetic marker n the early detection of HCC.