Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and it is one of the major causes of death. HCC is now a rather common malignancy in Egypt which usually develops on top of liver cirrhosis secondary to viral infection.The aim of this study was to investigate the potential role of Angiopoietin-2 (Ang-2) as a diagnostic non-invasive marker for HCC, in order to add a beneficial diagnostic value in patients with low levels of alpha-fetoprotein (AFP) and suspected to have HCC.This study was conducted on 30 patients with documented HCC using triphasic computerized tomography (CT) scan and histopathological assessment (when needed) and 30 cirrhotic patients with no evidence of HCC; as well as 30 healthy subjects who served as control group.We determined the level of AFP and Ang-2 for all cases together with full clinical assessment, liver biochemical profile, viral markers, conventional ultrasound (US), abdominal triphasic CT scan and guided liver biopsy for HCC cases with atypical CT pattern.We found that the diagnostic sensitivity of AFP at a cutoff of200 ng/ml was 24% and the specificity was 100%. The cutoff level of Ang-2 for diagnosis of HCC in this study was 8100 pg/ml, with a sensitivity and specificity of 70% and 80% respectively. Serum Ang-2 was significantly elevated in the HCC group than cirrhosis and control groups and in HCC patients with portal vein thrombosis than those without. There was a significant positive correlation between the number of hepatic focal lesions and the serum level of Ang-2. The combined use of the two markers (AFP and Ang-2) led to an increase in the sensitivity of AFP from 53.3% to 83.3%. Serum Ang-2 is elevated in patients with cirrhosis and further elevated in patients with HCC, so its use as an independent tumor marker in the diagnosis of HCC is to be considered. Simultaneous measurement of serum AFP and Ang-2 may enhance the sensitivity of HCC detection.