Objective To analyze the risk factors for the occurrence of pancreatic fistula after pancreaticoduodenectomy and provide theoretical basis for effective clinical reduction of postoperative complications. Methods We retrospectively analyzed the clinical data of 352 patients who underwent pancreaticoduodenectomy for cancer from September 2009 to September 2012 in Renji Hospital of Shanghai Jiaotong University School of Medicine, and divided the patients into pancreatic fistula group and non-pancreatic fistula group according to the presence or absence of pancreatic fistula after surgery. Univariate analysis and multivariate logistic regression analysis were performed to analyze various factors that may affect the occurrence of postoperative pancreatic fistula in the perioperative period. Results A total of 49 cases of pancreatic fistula occurred after pancreaticoduodenectomy, and the incidence of pancreatic fistula was 13.9% (49/352). After univariate and multifactorial analyses, the occurrence of postoperative pancreatic fistula was not related to the patients’ gender and age, history of diabetes, operation time, intraoperative bleeding, whether vascular resection and reconstruction were performed, whether support tubes were left in the pancreatic duct, the time of pancreatic-intestinal anastomosis, and the mode of digestive tract reconstruction; while the pancreatic brittle texture, pancreatic duct diameter <3 mm, preoperative serum total bilirubin level >171 ixmol/L, preoperative jaundice lasting for more than The pancreatic texture, pancreatic duct diameter <3 mm, preoperative serum total bilirubin level >171 ixmol/L, preoperative jaundice lasting more than 8 weeks, and preoperative serum albumin level <30 g/L were independent risk factors for the development of postoperative pancreatic fistula (P value <0.05). Conclusion Pancreatic texture, pancreatic duct diameter, degree of preoperative jaundice, duration of jaundice and hypoproteinemia are risk factors affecting the occurrence of pancreatic fistula after pancreaticoduodenectomy.