Vascular endothelial growth factor (VEGF) is involved in both development and progression of several epithelial tumours, but its role in hepatocellular carcinoma (HCC) is unclear. Assessment of liver and blood levels of VEGF may provide further insights on angiogenesis in HCC. Tissue mRNA of VEGF-165, VEGF-189 and their receptor KDR was assessed by a semi-quantitative retro-transcriptase polymerase chain reaction, and expressed as target transcript/beta-actin ratio, in 29 patients with HCC, 26 with cirrhosis and 15 with chronic hepatitis. VEGF-165 was also measured by ELISA in plasma samples obtained from both hepatic and femoral veins in additional 58 patients, including 15 with HCC. The liver expression of mRNA of VEGF-165, VEGF-189 and KDR was higher in HCC than in chronic liver diseases (1.54 +/- 0.89 vs 0.62 +/- 0.47, P < 0.0001; 1.09 +/- 0.65 vs 0.64 +/- 0.54, P = 0.003; 1.30 +/- 1.09 vs 0.69 +/- 0.72, P = 0.014). VEGF-165 was higher in HCC tissue than in extra-tumoural tissues (1.44 +/- 0.31 vs 1.03 +/- 0.21, P = 0.0009) and in the cirrhotic tissue of HCC patients than in HCC-free cirrhosis (1.03 +/- 0.23 vs 0.45 +/- 0.45, P = 0.0002). Tissue VEGF-189 mRNA inversely correlated with tumour size and degree of tumour cell proliferation. The hepatic and femoral vein levels of VEGF-165 protein were significantly higher in HCC patients than in cirrhotic patients (66.7 +/- 57.1 vs 24.2 +/- 16.4 pg/mL, P = 0.0001 and 37.1 +/- 42.2 vs 13.5 +/- 9.6 pg/mL, P = 0.001). There was a gradient of VEGF-165 between hepatic and femoral veins in both HCC and cirrhosis. In conclusion, VEGF appears to be involved in the development of HCC and it could be a predictor of HCC development in patients with cirrhosis.