Patient: Male, 64 Final Diagnosis: Intrahepatic cholangiocarcinoma with pure squamous cell Symptoms: — Medication: — Clinical Procedure: — Specialty: — Objective: Rare disease Background: In the United States, approximately 2500 cases of cholangiocarcinoma occur each year. The average incidence is 1 case/100 000 persons each year. Surgical resection is the mainstay for the treatment of cholangiocarcinoma. The result of surgery depends on location of the tumor, extent of tumor penetration of the bile duct, tumor-free resection margins, and lymph node and distant metastases. There has been an increase in the incidence of intrahepatic cholangiocarcinoma (IHCC) globally over a period of 30 years from 0.32/100 000 to 0.85/100 000 persons each year. Epidemiologically, the incidence of IHCC has been increasing in the U.S. from year 1973 to 2010. Case Report: We are reporting a first case of primary intrahepatic cholangiocarcinoma of pure squamous cell histology. A 64-year-old man presented with right upper-quadrant pain, jaundice, and weight loss. Imaging studies revealed a large hepatobiliary mass, intrahepatic bile duct dilation, normal common duct, and absence of choledocholithiasis. Delayed-contrast magnetic resonance imaging of the abdomen showed peripheral enhancement of the central lesion, which is typical of cholangiocarcinoma in contrast to hepatocellular carcinoma or metastasis. Cancer antigen 19-9 was markedly elevated. Liver function tests were deranged. Endoscopic retrograde cholangiopancreatography showed high degree of left hepatic duct stricture. Brush cytopathology was positive for atypia. The patient underwent exploratory laparotomy for en-bloc resection of the hepatobiliary mass with colon resection, liver resection, and cholecystectomy. Histology revealed keratinizing squamous cell carcinoma. Based on these findings, a definitive diagnosis of well-differentiated squamous cell carcinoma of the intrahepatic bile duct was made. Conclusions: Squamous cell carcinoma of the biliary tree is very rare and the majority of tumors are adenocarcinomas. Cholangiocarcinomas containing a squamous cell component have a poor prognosis due to its aggressive behavior. However, prognosis of cholangiocarcinoma with pure SCC histology is unknown because this is the first case in the literature.