This study was performed to investigate factors determining tumor pressure (TP) in hepatocellular carcinoma (HCC) and a correlation of pressure gradient between TP and portal vein pressure (PVP) with tumor spread. TP and hepatic tissue pressure (HTP) were measured in 70 patients who underwent hepatic resection for HCC. Changes in TP after hepatic artery occlusion (HAO) or portal vein occlusion (PVO) were observed. HTP was elevated with worsening chronic liver disease, and exhibited a significant positive correlation with PVP. The TP was significantly higher in the encapsulated and the nonnecrotic HCCs. The pressure gradient (TP-PVP) was significantly greater in the encapsulated HCCs, especially in those with microscopic portal vein invasion (vp) or intrahepatic metastasis (im). HAO caused a greater decrease in TP than did PVO, with the decrease being particularly marked in the encapsulated HCCs. The TP of HCC was found to be regulated mainly by the presence or absence of a tumor capsule or necrosis, and partly by the hepatic arterial flow and PVP. Our study suggests that TP increases with capsule formation and that the pressure gradient between TP and PVP may be a causal factor in the dispersement of tumor cells into the portal vein.