Background The morbidity rate after pancreaticoduodenectomy remains high. The objectives of this retrospective cohort study were to clarify the risk factors associated with serious morbidity (Clavien–Dindo classification grades IV–V), and create complication risk calculators using the Japanese National Clinical Database. Methods Between 2011 and 2012, data from 17,564 patients who underwent pancreaticoduodenectomy at 1,311 institutions in Japan were recorded in this database. The morbidity rate and associated risk factors were analyzed. Results The overall and serious morbidity rates were 41.6% and 4.5%, respectively. A pancreatic fistula (PF) with an International Study Group of Pancreatic Fistula (ISGPF) grade C was significantly associated with serious morbidity (P < 0.001). Twenty‐one variables were considered statistically significant predictors of serious complications, and 15 of them overlapped with those of a PF with ISGPF grade C. The predictors included age, sex, obesity, functional status, smoking status, the presence of a comorbidity, non‐pancreatic cancer, combined vascular resection, and several abnormal laboratory results. C‐indices of the risk models for serious morbidity and grade C PF were 0.708 and 0.700, respectively. Conclusions Preventing a PF grade C is important for decreasing the serious morbidity rate and these risk calculations contribute to adequate patient selection. HighlightAoki and colleagues clarified the risk factors associated with serious morbidity (Clavien‐Dindo classification grades IV–V) and created risk calculators using a Japanese nationwide database of 17,564 patients after pancreaticoduodenectomy. Preventing pancreatic fistula grade C is important for reducing serious morbidity and these risk calculations contribute to more appropriate patient selection.