In most patients with perihilar cholangiocarcinoma (PHCC), major hepatectomy and extrahepatic bile duct resection are needed for surgical radicality, and a high risk of hepatic insufficiency exists. This study aims to develop a prediction model for post-hepatectomy liver failure (PHLF) in patients with PHCC. A total of 143 patients who underwent major liver resection and extrahepatic bile duct resection for PHCC between October 2001 and December 2013 were included. Clinically relevant PHLF was defined as liver failure corresponding to grade B or C of the International Study Group of Liver Surgery criteria. Multivariate logistic regression was used to develop the PHLF risk model. Model performance was evaluated internally using the area under the curve analysis (discrimination) after 1000 bootstrap resampling and the Hosmer-Lemeshow goodness-of-fit test (calibration). Post-hepatectomy liver failure occurred in 43.4% of patients (n=62). In multivariate analysis, PHLF was significantly associated with future liver remnant ratio (odds ratio [OR] per 10%=0.68, 95% confidence interval [CI] 0.51-0.88), intraoperative blood loss (OR per 1L=1.82, 95% CI 1.11-3.17), and preoperative prothrombin time>1.20 (OR=3.22, 95% CI 1.15-9.97). The PHLF risk score model showed good discrimination (area under the curve=0.708, 95% CI 0.623-0.793) and calibration (P=0.227). The risk model proposed in this study accurately predicted PHLF in patients with PHCC. This offers surgeons a practical guide to quantitative risk assessment of hepatic insufficiency and aids decision-making in surgical treatment and perioperative management.