Cholestasis and injury of interlobular bile ducts occur during rejection of human hepatic allografts. However, knowledge of the nature and progression of bile duct injury during rejection remains incomplete. To define the role of inflammation in bile duct damage, we assessed the light microscopic appearance of hepatic tissue from selected patients in whom allograft failure was solely due to rejection. Nine patients with rejection were easily separated into two groups based on the duration of the allograft survival. The first group (early rejection) consisted of five patients in whom rejection occurred between 13 and 36 days. The second group (late rejection) consisted of four patients in whom rejection occurred between 170 and 912 days. Early rejection was characterized by distortion of bile ducts by adjacent inflammatory cell infiltrates, cytological changes of bile duct epithelial cells and occasionally by frank mononuclear cell inflammation of the epithelium with destruction of the duct. Late rejection was characterized by nonsuppurative destructive cholangitis culminating in the disappearance of interlobular bile ducts. Both groups exhibited histological cholestasis, intact limiting plates, preservation of hepatocytes and positive orcein stains for copper-binding protein. We conclude that the dominant histopathological feature of hepatic allograft rejection is progressive, nonsuppurative destructive cholangitis.