Background: Resection of periampullary carcinoma can be performed in fifty to sixty percent of people, although pancreatic cancer resection is a viable treatment option in ten to twenty percent of cases. Periampullary carcinoma has a more favorable prognosis after surgical resection. About 0.2% of all gastrointestinal tumors are periampullary adenocarcinoma (PAAC), which involve adenocarcinoma (AC) of the pancreatic head, the distal common bile duct (CBD), the second portion of the duodenum, plus the ampulla of Vater. Although relatively uncommon, the incidence of periampullary tumors has been on the rise in recent years. Aim of the work: This study aimed to determine the most important predictors of fistula formation after pancreaticoduodenectomy for periampullary carcinoma. Methods: This was observational study that included 20 individuals to undergo pancreaticoduodenectomy for periampullary carcinoma in Helwan University Hospitals. Results: There was highly significant variation among the two groups concerning drain amylase plus drain lipase. Conclusion: Comprehensive care to achieve POPF reduction is essential for individuals with greater drain amylase levels, which were associated with a higher fistula risk grade. Future research must involve a multicenter investigation to validate as well as to standardize amylase levels.