ABSTRACT Background Grade C pancreatic fistula (PF) is the most dangerous complication after pancreaticoduodenectomy (PD) and had not been identified on the early post-operative day yet. In this study, we aimed to introduce a new approach to distinguish grade C from grade B PF by using features on the 5th post-operative day’s computerized tomography (CT). Materials and Methods A bi-centric prospective cohort study was conducted from August 2021 to October 2023 at the University Medical Center (UMC) and Cho Ray Hospital, Viet Nam. Patients who diagnosed pancreatic fistula, underwent a CT scan on the 5th postoperative day were followed - up within 90 days after PD. The characteristics of CT scan images were analyzed to differentiate both grades of PF. Results During 26 months, 77 patients with periampullary cancer underwent PD and met the criteria of the study (46 males, mean age: 57.1 ± 13.7). Of these, 52 patients had biochemical PF and 25 had CRPF (18 grade B PF and 7 grade C PF). Specifications on the 5th postoperative day’s CT scan that can discriminate grade C from grade B included: fluid diffusing throughout abdomen, retroperitoneal abscess, hematoma beneath the liver, size of the fluid collection next to the pancreas (p = 0.031) and size of pancreatojejunostomy anastomosis dehiscence (p = 0.045). Conclusions Features on CT scan could be used to identify grade C from the 5th postoperative day. This result can help surgeons to make a plan for carefully follow-up those patients and indicate re-operation at an early stage.