Using the multiple indicator dilution approach, events occurring in the microvascular bed can be characterized in experimental animals with different types of cirrhosis and in man. Intrahepatic shunts can be found shunting blood away from sinusoids in both cirrhotic patients and cirrhotic animals. Such shunts were present in about one-third of cirrhotic patients with portal hypertension, and occurred mainly between the portal vein and hepatic veins. In cirrhotics, portohepatic anastomoses are usually large in diameter (more than 20 micron in diameter). Collagenization of the space of Disse and the progressive transformation of sinusoids into capillary-like channels decrease the extravascular space accessible to albumin and probably to other large molecules and protein-bound substances. However, unlike findings obtained in well-capillarized organs, these sinusoidal changes do not appear to limit the diffusion of sucrose, water, and lipophilic substances, such as lidocaine in the extravascular and intracellular spaces. The pattern observed for labeled sucrose curves following hepatic artery injection in cirrhotic patients could be secondary to the passage through the dense peribiliary capillary plexus originating from the enlarged arterial bed in cirrhosis. The difference in the perfusion of cirrhotic nodules with regard to the portal venous and hepatic artery routes introduces important new concepts in the overall mechanism of the elimination of endogenous and exogenous substances by the cirrhotic liver: blood entering the liver by the two afferent vessels will not flow through the same vascular bed before reaching the efferent hepatic veins.