Background: Post-hepatectomy liver failure (PHLF) is a serious complication after major hepatectomy with extrahepatic bile duct resection (Hx with EBDR) that may cause severe morbidity and even death. The purpose of this study was to compare several criteria systems as predictors of PHLF-related mortality following Hx with EBDR for perihilar cholangiocarcinoma (PHCC). Methods: The study cohort consisted of 222 patients who underwent Hx with EBDR for PHCC. We compared several criteria systems, including previously established criteria (the International Study Group of Liver Surgery (ISGLS) criterion; and the “50-50” criterion), and our institution’s novel systems “Max T-Bili” defined as total bilirubin (T-Bili) >7.3 mg/dL during post-operative days (POD) 1–7, and the “3-4-50” criterion, defined as total bilirubin >4 mg/dL and prothrombin time <50% on POD #3. Results: Thirteen patients (5.8%) died from PHLF-related causes. The 3-4-50 criterion showed high positive predictive values (39.1%), the 3-4-50, Max T-Bili, and 50-50 criterion showed high accuracies (91.7, 86.9, and 90.5%, respectively) and varying sensitivities (69.2, 69.2, and 38.5% respectively). Conclusions: The 3-4-50, Max T-Bili, and 50-50 criterion were all useful for predicting PHLF-related mortality after Hx with EBDR for PHCC.