In the mandatory nationwide Dutch Pancreatic Cancer Audit, rates of major complications and Failure to Rescue (FTR) after pancreatoduodenectomy between low- and high-mortality hospitals are compared, and independent predictors for FTR investigated. Patients undergoing pancreatoduodenectomy in 2014 and 2015 in The Netherlands were included. Hospitals were divided into quartiles based on mortality rates. The rate of major complications (Clavien-Dindo ≥3) and death after a major complication (FTR) were compared between these quartiles. Independent predictors for FTR were identified by multivariable logistic regression analysis. Out of 1.342 patients, 391 (29%) developed a major complication and in-hospital mortality was 4.2%. FTR occurred in 56 (14.3%) patients. Mortality was 0.9% in the first hospital quartile (4 hospitals, 327 patients) and 8.1% in the fourth quartile (5 hospitals, 310 patients). The rate of major complications increased by 40% (25.7% vs 35.2%) between the first and fourth hospital quartile, whereas the FTR rate increased by 560% (3.6% vs 22.9%). Independent predictors of FTR were male sex (OR = 2.1, 95%CI 1.2–3.9), age >75 years (OR = 4.3, 1.8–10.2), BMI ≥30 (OR = 2.9, 1.3–6.6), histopathological diagnosis of periampullary cancer (OR = 2.0, 1.1–3.7), and hospital volume <30 (OR = 3.9, 1.6–9.6). Variations in mortality between hospitals after pancreatoduodenectomy were explained mainly by differences in FTR, rather than the incidence of major complications.