The present study investigated whether, in rats with portal hypertension due to cirrhosis of the liver induced by carbon tetrachloride, blood volume restitution following a hemorrhage produces an increase of portal pressure beyond control values, as observed in rats with prehepatic portal hypertension. Since carbon tetrachloride-induced cirrhosis caused mild portal-systemic shunting, in some of the cirrhotic rats (12 of 29 rats) portal-systemic shunting was enhanced by a transient (4 days) partial constriction of the portal vein, which was removed 1 week prior to the study. After baseline measurements of portal pressure and arterial pressure, 15 ml per kg of blood were withdrawn at a rate of 0.3 ml per min and reinfused 15 min later. After blood reinfusion, portal pressure and arterial pressure were measured again, and cardiac output, regional blood flows and portal-systemic shunting were determined using radioactive microspheres. Portal-systemic shunting was 78 ± 11% of total blood flow in the cirrhotic rats that had temporary portal vein constriction, but only 5 ± 2% (p < 0.001) in those that did not. Blood volume restitution in low-portal-systemic shunting rats did not produce any significant modification in splanchnic or systemic hemodynamics. However, in rats with high portal-systemic shunting, blood volume restitution produced a significant increase in portal pressure (from 9.9 ± 0.9 to 13.5 ± 0.9 mmHg, p < 0.02). This increase in portal pressure after blood reinfusion was due to a significant increase in portal vascular resistance (from 1.3 ± 0.2 to 1.9 ± 0.2 mmHg per ml per min per 100 gm, p < 0.05), since no significant changes were observed in either portal blood flow or systemic hemodynamics. Our results show that blood volume restitution after a hemorrhage worsens the portal hypertension syndrome in cirrhotic rats with high portal-systemic shunting but not in those with low portal-systemic shunting, thus demonstrating that the extent of portal-systemic shunting is an important mediator of this deleterious effect.