Vacuolation of liver cells, which is often seen in patients with right-sided heart failure, is sometimes confused with fatty change, but the contents are components of blood. This study was undertaken using an isolated rat liver perfusion model to clarify the pathogenesis of vacuolation of liver cells. It has been demonstrated that (1) hypoxia alone cannot cause vacuolation; (2) elevation of the sinusoidal pressure leads to vacuoles in liver cells, irrespective of the oxygen content of the perfusate; and (3) the number and size of vacuoles are proportional to the height of the sinusoidal pressure, but not to the oxygen content of the perfusate. The reason why vacuolation generally appears in the pericentral area in patients with right-sided heart failure may be that the sinusoidal pressure in this area rises in parallel with the inferior vena cava pressure.