Background and Aims Hilar cholangiocarcinoma refer to a malignant tumor originating from the epithelial cells involving the left, right hepatic ducts, biliary confluence or the upper segment of the common hepatic duct. Due to the complex anatomy of the hilar region and its proximity to major vessels such as the portal vein and hepatic artery, this tumor is prone to vascular or neural invasion, and lymph node metastasis. Additionally, its inconspicuous location and lack of early specific symptoms often result in patients seeking medical treatment only when advanced symptoms like jaundice appear. Currently, surgical resection remains the primary effective treatment for improving prognosis. However, surgical management of hilar cholangiocarcinoma remains one of the most challenging tasks for hepatobiliary surgeons. Here, the authors report a case of hilar cholangiocarcinoma invading the stomach, duodenum, and pancreas, treated with total pancreatectomy and duodenectomy combined with total hepatectomy and orthotopic liver transplantation, aiming to provide further reference for the diagnosis and treatment of this disease.Methods The clinical data of a case of hilar cholangiocarcinoma, collaboratively treated by the PLA Rocket Force Characteristic Medical Center and Hebei Medical University Third Hospital were retrospectively analyzed. Relevant literature was reviewed and pertinent experiences and lessons learned from this case were summarized.Results The patient, a 51-year-old male with a history of hepatitis B, sought medical attention due to abdominal ascites. Abdominal exploration (revealing a tumor involving an inseparable region of the liver, pancreatic head, and hepatoduodenal ligament) and PET-CT scan (indicating a slightly low-density lesion with increased FDG metabolism in the right lobe of the liver, possibly involving the main portal vein and right branch, with no apparent distant metastasis) suggested a malignant tumor, but preoperative biopsy failed to provide a definitive diagnosis. After discussion, the patient underwent total pancreatectomy and duodenectomy combined with total hepatectomy and orthotopic liver transplantation (anastomosing the superior mesenteric vein with the donor portal vein and anastomosing the inverted splenic artery with the proper hepatic artery of the donor, due to preoperative CT indicating occlusion or tumor invasion of the portal vein and hepatic artery). The postoperative recovery was uneventful, and the pathology revealed moderately to well-differentiated cholangiocarcinoma of the hepatic hilar region involving the duodenum, stomach, and pancreas, with multiple neural invasions, no clear vascular tumor thrombus, and margins free of cancer. The patient died of gastrointestinal bleeding and infection 8 months after surgery.Conclusion Surgical resection remains the primary treatment for hilar cholangiocarcinoma. For patients ineligible for radical resection, liver transplantation is an option that can achieve R₀ resection, providing a potential opportunity for cure. However, there are currently still relatively few reported cases of combined total pancreaticoduodenectomy. The analysis and summary of this case will contribute to further exploration and practice in the future.