Background Post-pancreatectomy acute pancreatitis (PPAP) is a newly described clinical entity defined as elevated serum amylase sustained ≥ 48 h postoperatively, radiological findings consistent with acute pancreatitis, and associated clinically relevant features. This study aimed to investigate the incidence of PPAP and the rate of major complications after pancreatoduodenectomy (PD) in patients with only transiently elevated serum amylase. Methods A retrospective single-center observational study was conducted including consecutive patients ≥ 18 years of age undergoing PD at Karolinska University Hospital, between 2008 and 2020. Serum amylase on postoperative day (POD) 1 and 2 and records from computer tomography were analyzed and correlated with postoperative major complications by logistic regressions. Results Of some 1078 patients that underwent PD, 284 exhibited sustained elevated serum amylase (according to PPAP criteria) and 183 transiently elevated serum amylase on either POD1 or POD2. Of the patients with sustained elevated levels, 43% (n = 123) developed major complications, but only 6.3% (n = 18) showed findings consistent with acute pancreatitis on imaging. Of the 183 cases that exhibited only transiently elevated serum amylase on either POD1 or POD2, 32% (n = 58) developed major complications. Conclusion Sustained hyperamylasemia was observed in 26% of patients after PD, and an additional 17% of patients had a transient elevation of serum amylase postoperatively. Acute pancreatitis after PD may be underdiagnosed, partly by overlooking transiently elevated serum amylase and partly by requiring imaging that potentially fails to recognize mild but complication-prone acute pancreatitis.