ABSTRACT—The histologic significance of various changes in the bile ductal structures as observed by cytokeratin immunoperoxidase assay was studied in 122 patients with alcoholic liver disease (ALD) as a part of a large Veterans Administration Cooperative Study on alcoholic hepatitis. Four types of morphologic changes in the biliary structures were observed: 1) proliferation of interlobular bile ducts in the portal tracts; 2) marginal bile ductular proliferation at the periphery of the portal tracts; 3) appearance of bile duct type cells (“oval cells”) in the liver parenchyma; and 4) metaplasia of bile duct epithelium to cells resembling hepatocytes. These bile ductal changes correlated strongly with liver fibrosis (p = 0.0003; 0.0003; 0.05; 0.0035, for 1, 2, 3, and 4, respectively), cirrhosis (p<0.0001 for all four parameters), portal inflammation (p<0.0001 for 1, 2, and 4; p = 0.0024 for “oval cells“), and with overall histologic severity scores (p<0.0001; p = 0.0001; p = 0.0017; p = 0.0005, respectively). However, these changes did not correlate significantly with fatty change, parenchymal degeneration and necrosis, cellular infiltrate or Kupffer cell hyperplasia, suggesting that they are probably not the direct consequences of liver cell necrosis. Periportal piecemeal necrosis correlated significantly with both portal bile duct (p = 0.0041) and marginal (p = 0.0078) bile ductular proliferation. Among all these changes, only marginal bile ductular proliferation correlated significantly with Mallory bodies present both in the hepatocytes (p = 0.05) and the bile ducts (p = 0.01). Both marginal bile ductular proliferation and “oval cells” correlated significantly with clinical severity of the liver disease as determined by high serum bilirubin and prolonged prothrombin time (Maddrey's discriminant function). This study suggests that: 1) a variety of important morphologic changes occur in the bile ductal structures in ALD, particularly when fibrosis and cirrhosis develop; 2) “oval cells” and bile duct metaplasia are frequent in ALD and appear to be significantly related to the development of fibrosis and cirrhosis; 3) bile ductules are an integral component of piecemeal necrosis in ALD; 4) some of the bile ductal changes may influence the clinical outcome of