Alterations in the liver microcirculation were characterized by use of the multiple-indicator dilution technique in 25 cirrhotic patients undergoing hemodynamic evaluation of portal hypertension. Hepatic vein outflow dilution curves were obtained after portal vein or hepatic artery injections of a vascular reference substance (labeled erythrocytes) and of diffusible substances (labeled albumin and sucrose). In 23 of these patients (19 with alcoholic cirrhosis and 4 with postnecrotic cirrhosis), unimodal erythrocytes and albumin curves were obtained; the immediately accessible albumin space ranged from normal values (that were substantially larger than the erythrocyte space) to low values (that were little larger than the erythrocyte space). In parallel with this, the hepatic extraction of indocyanine green decreased and was correlated with the albumin space (r = 0.821, P less than 0.001). The form of labeled sucrose curves showed progressive changes indicating limited diffusion into the interstitial space. In contrast, bimodal curves were found in two patients (with macronodular cirrhosis); a large proportion of all labels appeared simultaneously in the early part of the outflow curves. Model analysis of the unimodal data indicated that the spectrum of findings could best be explained by progressive development of a barrier to exchange by progressive capillarization of the microvascular bed, and the form of the bimodal data suggested that large vessel shunting was occurring. Both changes, in turn, will contribute to the reduced extraction of protein-bound materials in cirrhosis.