Innervation of the liver with or without chronic liver disease was immunohistochemically studied. In normal liver tissues, gamma-enolase [neuron-specific enolase (NSE)]- and S-100 protein (S-100)-positive nerve fibers were found around hepatic arteries, portal veins, and bile ductules in the portal area, along the sinusoid, and around central veins inside the hepatic lobule. Neuropeptide Y (NPY)-immunoreactive (IR) nerve fibers were detected in close contact with hepatic arteries and portal veins in the portal area and along the sinusoid in the parenchyma. Vasoactive intestinal polypeptide (VIP)-IR nerve fibers were found in the portal area but were scarce in the parenchyma. VIP-IR nerve fibers were much fewer than NPY-IR fibers. In patients with chronic active hepatitis, NSE- and S-100-positive nerve fibers, as well as NPY-IR nerve fibers, proliferated in the enlarged portal area. In cirrhotic liver, NSE- and S-100-positive nerve fibers and NPY-IR fibers increased remarkably in the fibrous septa, whereas they decreased or vanished inside the pseudolobules. These findings suggest that, in chronic liver disease, intrahepatic nerve fibers change their distribution, accompanying the structural changes in the hepatic lobules.