Background and study aim: Hepatocellular carcinoma (HCC) is a hypervascular tumor and its progression is known to be closely related to angiogenesis. Angiopoietin-2 (Ang-2) is one of the angiogenic factors that may have a diagnostic value in HCC. Alpha-fetoprotein (AFP) serum levels are used for screening for HCC with limited success. This study aimed to evaluate diagnostic value in using angiopoietin-2 as a serum marker in HCC patients. Patients and Methods: 50 patients with HCC (G1), 20 patients with liver cirrhosis (G2), and 20 healthy control persons (G3) were included in this study. Serum AFP and Ang-2 levels were measured by enzyme-linked immunosorbent assay. Results: Serum Ang-2 levels in the HCC group (1523.54±886.46 pg/ml) was highly significantly elevated as compared to those with cirrhotic liver (222.55±153.60 pg/ml) and controls (138.35±54.09 pg/ml). The Ang-2 levels were significantly different between patients with liver cirrhosis and controls. In HCC patients, the serum Ang-2 levels in patients with portal vein (PV) thrombosis (n=7, 2164.0±960.85 pg/ml) and with large HCC (>5cm in diameter) (n=17, 2017.70±903.06 pg/ml) were significantly higher than those without PV thrombosis (n=43, 1274.47±727.56 pg/ml) and with small HCC (≤5cm in diameter) (n=33, 1268.97±773.93 pg/ml), while the serum AFP levels in patients with portal vein (PV) thrombosis (961.05±1007.70 ng/ml) and with large HCC (>5cm in diameter) (1000.81±1079.57 ng/ml) were not significantly higher than those without PV thrombosis (500.24±733.07 ng/ml) and with small HCC (437.87±611.02 ng/ml). Conclusion: Combined measurement of serum AFP and Ang-2 significantly increases the sensitivity and specificity of HCC detection rather than using of AFP or Ang-2 separately.