Introduction: In 2017 the International Study Group for Pancreatic Surgery (ISGPS) published a consensus definition of chyle leak (CL). Multicenter series assessing the ISGPS-CL definition are lacking and previous studies investigating risk factors for CL used different definitions and showed heterogeneous results. The aim of this study was to assess the clinical impact of the ISGPS-CL definition on incidence, the association with length of stay and mortality, and to assess risk factors of CL. Method: This observational cohort study included patients who underwent pancreatoduodenectomy from the mandatory nationwide Dutch Pancreatic Cancer Audit (2017-2019). Only clinically relevant CL (grade B/C) was included. Prolonged length of stay was defined as more than 14 days. Multivariable logistic regression models 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. After adjustment for confounders, CL was associated with a prolonged hospital stay (OR 2.84, 95% CI 1.85-4.36, p < 0.001). In multivariable analysis, CL was not related to in-hospital mortality. Vascular resection, i.e. arterial and/or venous resections (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) were identified as independent predictors for CL in multivariable analyses, whereas the number of lymph nodes resected and aortocaval lymph node sampling was not. Conclusion: Use of the ISGPS-CL definition is recommended for further studies, to adequately compare results. Risk factors should be taken into account in the postoperative follow-up.