Objective:The aim of this study was to assess the clinical impact and risk factors of chyle leak (CL).Background:In 2017, the International Study Group for Pancreatic Surgery (ISGPS) published the consensus definition of CL. Multicenter series validating this definition are lacking and previous studies investigating risk factors have used different definitions and showed heterogeneous results.Methods:This observational cohort study included all consecutive patients after pancreatoduodenectomy in all 19 centers in the mandatory nationwide Dutch Pancreatic Cancer Audit (2017–2019). The primary endpoint was CL (ISGPS grade B/C). Multivariable logistic regression analyses were performed.Results:Overall, 2159 patients after pancreatoduodenectomy were included. The rate of CL was 7.0% (n=152), including 6.9% (n=150) grade B and 0.1% (n=2) grade C. CL was independently associated with a prolonged hospital stay [odds ratio (OR)=2.84, 95% confidence interval (CI): 1.85–4.36,P<0.001] but not with mortality (OR=0.3, 95% CI: 0.0–2.3,P=0.244). In multivariable analyses, independent predictors for CL were vascular resection (OR=2.1, 95% CI: 1.4–3.2,P<0.001) and open surgery (OR=3.5, 95% CI: 1.7–7.2,P=0.001). The number of resected lymph nodes and aortocaval lymph node sampling were not identified as predictors in multivariable analysis.Conclusions:In this nationwide analysis, the rate of ISGPS grade B/C CL after pancreatoduodenectomy was 7.0%. Although CL is associated with a prolonged hospital stay, the clinical impact is relatively minor in the vast majority (>98%) of patients. Vascular resection and open surgery are predictors of CL.