Background and Aim: The most common form of primary liver cancer in adults is hepatocellular carcinoma (HCC), and it is the most common cause of death in people with cirrhosis. The mammalian Sir2 family or sirtuins is formed of a cluster of highly conserved proteins triggering nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase activity which target histone and non-histone substrates including enzymes, transcription regulators, tumor suppressors, cell signaling proteins and DNA repair proteins. Seven human sirtuins have been identified and named SIRT1-7.  SIRT1 has been regarded as a tumor promoter due to its increased expression in some types of cancers and its role in the inactivation of proteins involved in tumor suppression and DNA damage repair.We aimed to estimate the level of SIRT-1 in the blood of HBV, HCV, and HCC patients, to investigate the possible role of SIRT-1 in the pathogenesis of HCC and to determine the role of SIRT-1 as a tumor marker or pomoter compared to other markers like α-feto protein. Subjects and Methods: This study was performed in Internal Medicine department Beni-Suef Hospital. Our study included 160 individuals; divided into four groups; group A (healthy control), group B (HBV patients), group C (HCV patients) and group D (HCC patients). The serum level of SIRT-1 was assessed and compared in all groups and correlate its level as a tumor marker with the other marker α-fetoprotein. Results: There was significant increase in SIRT-1 levels in HBV, HCV and HCC group as compared to control (p value <0.001). There was significant increase in SIRT-1 in HCV and HCC groups as compared to HBV group (p value <0.001). There was significant increase in SIRT-1 levels in HCC group as compared to HCV group (p value <0.001). There was positive correlation between α - feto protein and SIRT-1in HCC group only but no correlation in others groups. Conclusion: Our study demonstrated that SIRT-1 is overexpressed in HCC patients compared to chronic noncancerous viral liver parenchyma diseases, so it may be included in pathogenesis of HCC. SIRT-1 may have matchable specificity and sensitivity as AFP in HCC patients.