BACKGROUND: HCC is a primary tumor of the liver. It is one of the most common malignancies in adults. OBJECTIVE: Assessment of DNA methylation of BMP4, TSPYL5, APC1 and p16 genes in Egyptian hepatocellular carcinoma patients. METHODS: The present study included 180 subjects classified into: group (I) 60 HCC patients, group (II) 60 chronic liver disease patients with chronic HCV infection who were diagnosed by presence of HCV Abs for more than 6 months and quantitative PCR for HCV RNA and group (III) 60 apparently healthy volunteers as control subjects. For all participants, the following was done: Routine lab investigation including CBC, PT, PC, AST, ALT, ALP, albumin, Bilirubin, creatinine, AFP, abdominal ultra sonography, Spiral triphasic CT, and molecular assessement of p16, TSPYL5, ACP1, BMP4 methylation status. RESULTS: Gene expression by RT-PCR technique among studied groups; APC1, BMP4, TSPYL5, and P16 were statistically significant (p < 0.001) in HCC compared to control. CONCLUSIONS: Hypermethylation of p16, ACP1, BMP4, and TSPYL 5 are common events in patients with HCC and could be used as potentially detectable biomarkers in HCC...