AIM: To study the relationship between hypoxia or epidermal growth factor (EGF) and the overexpression of vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) and the signal transduction pathway of the transcription of VEGF in hepatoma cells. METHODS: Cobalt chloride and recombinant human EGF were used to stimulate the hepatoma cell lines HepG2. VEGF mRNA was detected by using of semi-quantitative polymerase chain reaction (RT-PCR). Specific inhibitors of phosphatidylinositol 3-kinase (PI3K) and p42/p44 mitogen activated protein kinase (MAPK) were used to observe the effects of the two kinases on the regulation of the transcription of VEGF in hepatoma cells. RESULTS: The expression of VEGF mRNA in HepG2 cells cultured in serum-free mediumwas 0.117. However, 100 nmol/L cobalt chloride for 24 h increased the expression of VEGF mRNA and VEGF mRNA increased gradually with the increase of the concentration and duration of cobalt chloride. Also, 25ng/mL recombinant human EGF stimulated the expression of VEGF in HepG2 cells and the expression increased with the increase of EGF concentration. 5nmol/L LY294002 inhibited the expression of VEGF stimulated by cobalt chloride or recombinant human EGF and the inhibition decreased step by step with increase of the concentration of LY294002. But even 20 mol/L LY294002 could not completely block theexpression of VEGF. In contrast, PD98059 had no inhibitory effects on the transcription of VEGF stimulated by cobalt chloride or recombinant human EGF. CONCLUSION: The overexpression of VEGF in HCC could be promoted by hypoxia and EGF expression in HCC. The signal transduction pathway of VEGF transcription in HepG2 cells may be through PI3K pathway, but not through p42/p44 MAPK pathway.