Chronic hepatitis C virus (HCV) infection is associated with the production of serum cytokines, including transforming growth factor (TGF)-beta2. Despite the occurrence of hepatic angiogenesis in liver conditions, the role of HCV proteins in this context is currently unknown. We demonstrated that the development of hepatic neoangiogenesis in patients infected with HCV is associated with the expression of TGF-beta2 and vascular endothelial growth factor (VEGF) and with activation of endothelial cells, as evidenced by CD34 expression. The analysis of liver biopsies of HCV-positive and HCV-negative patients using immunostaining showed significant elevation of TGF-beta2, VEGF, and CD34 expression in patients who were HCV-positive. Using an HCV established culture system, we confirmed further the production of both TGF-beta2 and VEGF proteins, in the hepatoma cell lines HepG2 and Huh7 by transfection with full-length HCV RNA (JFH1) or by the regulated expression of core. In addition, regulated expression of core protein in HepG2 or Huh7 cells was found to induce expression and activation of the transcription factor E2F1 and apoptosis signal-regulating kinase 1 (ASK1), activation of c-jun-N-terminal kinase (JNK) and p38, and extracellular-regulated kinase (ERK), and transcription factors activator protein 1 (AP-1), activating transcription factor 2 (ATF-2), cyclic adenosine monophosphate response element binding (CREB), E2F1, hypoxia inducing factor 1 alpha (HIF-1alpha), and specificity protein 1. Furthermore, data obtained from inhibitor experiments revealed the importance of E2F1 and ASK1 in the modulation of core-induced activation of JNK and p38 pathways and suggested an essential role for JNK, p38, and ERK pathways in the regulation of core-induced production of TGF-beta2 and VEGF proteins. Thus, our data provide insight into the molecular mechanisms whereby core protein mediates the development of hepatic angiogenesis in patients with chronic HCV infection.