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BACKGROUND The management of complications after major hepatectomy in perihilar cholangiocarcinoma may not always be successful, leading to failure to rescue. The present study seeks to identify independent risk factors for failure to rescue after major hepatectomy in perihilar cholangiocarcinoma. METHODS We retrospectively analyzed the postoperative course of all consecutive patients who underwent major hepatectomy in a curative intent for perihilar cholangiocarcinoma between 2005 and 2019 at our department. A multivariate logistic regression analysis was performed to identify independent risk factors for failure to rescue. RESULTS Of 287 patients, 186 (65%) had major complications (Dindo-Clavien grade ≥IIIa), of which 142 (76%) were grade IIIa to IVb (rescue group). Failure to rescue (FTR group, Dindo-Clavien grade V) occurred in 44 of 186 patients (24%). Age >65 years (odds ratio = 4.001, 95% confidence interval 1.025-15.615, P = .046) and right-sided resection (odds ratio = 17.040, 95% confidence interval 1.926 - 150.782, P = .011) were independently associated with failure to rescue. Preoperative carbohydrate antigen 19-9 levels >100 kU/mL as well as preoperative chemotherapy appear to increase odds for failure to rescue as well; however, the association was short of statistical significance (P = .070 and .079, respectively). CONCLUSIONS Elderly patients as well as patients undergoing right-sided hepatectomy for perihilar cholangiocarcinoma with high preoperative carbohydrate antigen 19-9 levels are at high risk for failure to rescue. Thus, patients should be assessed critically preoperatively. Postoperatively, close monitoring, especially of patients who are at risk, is mandatory.