Background and objectives: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer related mortality worldwide. The identification of new high-sensitivity and high-specificity markers for HCCis essential. Annexin A2 (ANXA2) plays an important role in the pathogenesis of multiple malignancies particularly HCCs and its expression strongly also affects the outcomes of HCC patients. This study aimed to investigate the clinical utility of hepatic and circulating Annexin A2 expression levels as a novel diagnostic marker of HCC and to correlate its level with alpha fetoprotein (AFP), the current marker ofHCC. Patients and methods: A total number of 40 patients(6 patients with chronic hepatitis, 8 patients with liver fiberosis, 6 patients with liver cirrhosis, 8 patients with early HCC and 12 patients with late HCC). The same number of age and sex matched healthy people was enrolled as a control group. All patients and controls were subjected to full medical history, complete medical examination abdominal sonography, laboratory investigations including liver function tests, AFP, platelet count, Prothrombin time and concentration, HBsAg, anti-HCV and serum HCV RNA quantitation by real time PCR. Liver biopsies were done for all patients. Evaluation of serum ANXA2 level for all patient and controlgroups was detected by using a human ANXA2 ELISA kit. Analyzing the ANXA2 expression at mRNA and protein levels was detected for patient groups by using RT-PCR by immunohistochemistry staining, respectively. Results: Serum ANXA2was significantly increased in all patient groups (except for chronic hepatitis group) compared to the control group (P<0.01). The serological evaluation and expression of ANXA2 levels were significantly increased in early HCC compared to serum AFP. ANXA2 expression was localized in both cell membrane and cytoplasm in HCC tissue, not detected in normal tissues and limited to some hepatocytes in chronic hepatitis patients. Over expression of ANXA2 mRNA levelwas present in HCC tissues compared to other patient groups (P<0.001). There was a significant relation with HCV infection, (P<0.001) when comparing ANXA2 values among positive and negative HCV RNA in HCC patients. No correlations were found between serum ANXA2 levels with serum AST,ALT, platelet count, INR and HBsAgin comparison to controls. Conclusion: Our results demonstrated increased levels of ANXA2 in both of tissues and sera of HCC patients and also in both AFP-positive and-negative cases. Results of serumANXA2 was concomitant with hepatic ANXA2 expression by RT-PCR and immunocytochemistry staining. Remarkably, Combination of conventional serum marker AFP with serumANXA2 may complement and benefit for early HCC detection.