Differential diagnosis of sclerosing cholangiocarcinomas of the common hepatic duct (Klatskin tumors). Although it is recognized that some other lesion may be the cause, a presumptive diagnosis of Klatskin tumor is usually made when a focal stenotic lesion of the common hepatic duct is seen on a cholangiogram of a jaundiced patient. Biopsy is so often nondiagnostic that decisions about therapy are usually made on the basis of the imaging tests and lack of evidence for some other disease. Because the accuracy and consequences of this strategy have never been tested, we contrasted the preoperative diagnosis of Klatskin tumor with the final diagnosis in 98 consecutive patients treated from 1985 to 1990. Preoperative investigations included ultrasound and computed tomographic scans, percutaneous transhepatic cholangiography, endoscopic retrograde cholangiopancreatography, and angiography. Sclerosing cholangiocarcinomas of the bile duct were correctly diagnosed in 68 cases. The final diagnosis was other than a sclerosing adenocarcinoma in 30 (31%) cases. There were 5 papillary bile duct carcinomas, 12 gallbladder carcinomas invading the bile duct, 5 metastatic tumors to the bile duct, 2 cases of Mirizzi syndrome, 3 granulomas, and 3 cases of idiopathic benign focal stenosis. Patients with papillary adenocarcinomas had an extensive filling defect of the duct, which was often thought to be unresectable. However, four of these five lesions could be completely excised, and the tumor was confined to the duct wall in all four. The outcome of surgical treatment of the other eight patients with benign lesions was good in most cases. These findings demonstrate the pitfalls of assuming that a focal stenosis of the hepatic duct represents a sclerosing adenocarcinoma. The diagnosis is much less specific than is generally thought, so there is considerable opportunity for mismanaging such patients. 