Hepatocellular carcinoma (HCC) is becoming one of the most common malignant tumors worldwide and is characterized by a high vascularity. Angiogenesis, formation of new microvessels, is critical for the growth and progression of various human solid tumors. Vascular endothelial growth factor (VEGF) and angiopoietins (Ang1 and Ang2) are endothelial cell-specific vasculogenic and angiogenic growth factors, but their expression and roles in HCC have not been extensively explored. The aim of this study was to determine the expression and cellular localization of VEGF, Ang1, and Ang2 in specimens of resected human HCC using in situ hybridization and immunohistochemical staining and to examine their relationship to microvessel density (MVD) and tumor size. We also investigated whether mutation of p53 protein might affect the expression of the above angiogenic growth factors. VEGF and Ang2 were strongly expressed and localized predominantly to cancer cells, whereas Ang1 was detected in supportive cells of large blood vessels, stromal cells, endothelial cells, and tumor cells. Expression of the VEGF protein and the Ang2 (but not Ang1) mRNA were strongly correlated with MVD (P <.05, P =.001) and tumor size (P <.05). There was also a strong correlation between VEGF protein and Ang2 mRNA expression (P <.001). However, no significant correlation was found between overexpression of p53 and the expression of VEGF, angiopoietins, or MVD. These findings suggest that overproduction of the angiogenic growth factors VEGF and Ang2 by HCC cells may increase vascularity and tumor growth in a paracrine manner. Our findings also suggest that interaction between VEGF and Ang2 may play a critical role in tumor angiogenesis in HCC.