Background: Pancreaticoduodenectomy (PD), a complex operation with a high morbidity rate, especially pancreatic fistula, is still the standard treatment for resectable pancreatic head, ampullary, distal bile duct, and duodenal tumours. Despite improvements in pancreatic fistula detection and treatment, it still has a significant death rate. As a result, it is critical to address the causes of pancreatic fistula for which this study was created. Objective: This study aimed to address the different risk factors affecting the incidence of pancreatic leakage post pancreaticoduodenectomy. Subjects and Methods: This is a retrospective case-control study that included all cases that experienced pancreaticoduodenectomy during the period from January 2014 to December 2021 at the National Cancer Institute (NCI), Cairo University. The cases have been categorized into two groups (cases who developed pancreatic leakage and those who did not develop it). Both groups were compared for the possible risk factors: age, gender, tumour size, LNs positivity, laboratory findings (HB, Albumin), neoadjuvants received, surgical techniques (anastomosis technique, vein resection, texture of pancreatic remnant), and postoperative nutrition plan used. Results: Ninety-five cases of pancreaticoduodenectomy were done during the study period. Among them, 35 cases had developed postoperative pancreatic fistula (POPF). A significantly higher pancreatic fistula incidence was associated with the female gender, preoperative haemoglobin levels of < 12 gm/dl and albumin levels of < 3.6 gm/dl, along with soft pancreatic texture. Conclusion: Pancreaticoduodenectomy is an operation with a high morbidity rate. Female gender, low HB and albumin levels, and soft pancreatic texture are risk factors for developing pancreatic fistula.