Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world with a 5 year survival rate of less than 5% and an incidence of at least one million new patients per year.Incidence of HCC in Egypt is currently increasing, which may be the result of a shift in the relative importance of HBV and HCV as primary risk factors. Objective: The aim of this work is to assess use of serum LINE-1 hypomethylation as a diagnostic and prognostic marker for HCC.Methods: The present study was performed on ninety patients and 10 healthy subjects; fifty patients had hepatocellular carcinoma, twenty patients had liver cirrhosis and twenty patients had chronic hepatitis C. Serum LINE-1 hypomethylation measurement was performed including DNA preparation and measurement of hypomethylationResults: -Serum LINE-1 hypomethylation was a statistically highly significant (p< 0.01) in HCC group when compared with the control groups. At cut off value of 60 percent (Best cut off) Serum LINE-1 hypomethylation yields a sensitivity, specificity, positive predictive value and negative predictive values of 46%, 95%, 95.83%, and 41.30 respectively.Hypomethylation values is significantly higher in multiple tumors, Tumor size 5 or > 5cm, and in patients with PVT than in single tumors, Tumor size <5 cm and patients with no PVT.Conclusion: Serum LINE-1 hypomethylation can serve as prognostic marker of HCC.Serum LINE-1 hypomethylation is more valuable than alpha fetoprotein as a prognostic marker of HCC.