Histopathological features of nonsuppurative destructive cholangitis have been described in primary biliary cirrhosis, chronic graft-vs-host disease, and chronic rejection of human liver allografts. To determine whether or not susceptibility to injury of interlobular bile ducts was related to the original hepatobiliary disease requiring transplantation, we compared the histopathology of allografts transplanted into two groups of patients. The first group consisted of patients whose original hepatobiliary diseases primarily affect bile ducts: primary biliary cirrhosis, sclerosing cholangitis, and biliary atresia. The second group consisted of patients whose original hepatobiliary diseases do not result in injury to interlobular bile ducts. In 32 liver allografts studied histopathologically, the original disease did not recur. Interlobular bile duct damage occurred, however, in 17 of the 32 and resembled that seen in primary biliary cirrhosis. The spectrum of bile duct injury included mononuclear inflammation of the bile duct epithelium, destruction of the bile duct epithelium, and dissolution of the bile duct. There was no relationship between the frequency or severity of bile duct damage and original hepatobiliary disease, age, sex, duration of allograft survival, or cause of death. We conclude that nonsuppurative destructive cholangitis occurs frequently in liver allografts and represents one component of allograft rejection. This lesion resembles, in many respects, that seen in primary biliary cirrhosis so that histopathological differentiation may be difficult.