BACKGROUND/AIMS: Hepatic stellate cells (HSCs) in the hepatocellular carcinoma are responsible for tumor encapsulation as a host defense mechanism. Recently, it was suggested that HSCs might play an important role in hepatic angiogenesis. Thus, HSCs in the HCC may be involved in tumor angiogenesis and pathogenesis of hepatic carcinogenesis. The purpose of this study was to examine the involvement of activated HSCs in the angiogenesis of hepatoma. METHODS: We investigated the effect of human HSC conditioned medium (CM) on the endothelial cell proliferation with or without stimulation of HepG2 CM, using [3H] thymidine incorporation assay. Additionally, we investigated the effect of HepG2 CM on HSCs proliferation and messenger RNA (mRNA) expression of various pro-angiogenic factors such as interleukin 8 (IL-8), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) in HSCs. RESULTS: HSC CM caused a significant increase in DNA synthesis in human umbilical vein endothelial cells (HUVEC). The endothelial proliferation effect of HSCs was augmented by HepG2 CM. HepG2 CM significantly increased HSCs proliferation and stimulated IL-8 and bFGF mRNA expression in HSCs. CONCLUSIONS: HSCs promote endothelial proliferation through various soluble factors. The soluble factors secreted in HepG2 stimulate HSC proliferation and up-regulate mRNA expression of proangiogenic factors. This result suggests that HSCs may play an important role in the angiogenesis of hepatoma.