Endothelin-1 (ET-1) may mediate increased resistance to hepatic sinusoidal blood flow. We evaluated the hepatic distribution of ET-1 in patients with idiopathic portal hypertension (IPH), in which liver architecture may be normal, and in patients with cirrhosis, in which distortion of hepatic sinusoidal architecture is prominent. Immunohistochemistry and in situ hybridization were used to localize ET-1 in hepatic tissue of patients with IPH and cirrhosis. ET-1 was measured in plasma from a peripheral vein, the hepatic vein, and the portal vein of patients with cirrhosis of the liver and controls. On immunohistochemistry and in situ hybridization, ET-1 was localized to periportal hepatocytes and sinusoidal cells in patients with IPH and cirrhosis. Minimal positive staining for ET-1 was observed in control livers. Plasma ET-1 levels were significantly greater in patients with cirrhosis than in controls. In patients with cirrhosis, ET-1 was greater in the hepatic vein compared with the portal vein. However, the level of plasma ET-1 in patients with cirrhosis did not correlate with either the presence of ascites or portacaval pressure gradient. We conclude that in IPH, ET-1 is localized to sites in which it can modulate intrahepatic resistance. In late stages of cirrhosis, ET-1 may not modulate resistance. We speculate that vascular resistance in late stages of cirrhosis probably results from distortion of hepatic architecture.