BACKGROUND As one of the major abdominal operations, pancreaticoduodenectomy (PD) involves many organs. The operation is complex, and the scope of the operation is large, which can cause significant trauma in patients. The operation has a high rate of complications. Pancreatic leakage is the main complication after PD. When pancreatic leakage occurs after PD, it can often lead to abdominal bleeding and infection, threatening the lives of patients. One study found that pancreatic leakage was affected by many factors including the choice of pancreaticojejunostomy method which can be well controlled. OBJECTIVE To investigate the choice of operative methods for pancreaticojejunostomy and to conduct a multivariate study of pancreatic leakage in PD. METHODS A total of 420 patients undergoing PD in our hospital from January 2014 to March 2019 were enrolled and divided into group A (n = 198) and group B (n = 222) according to the pancreatointestinal anastomosis method adopted during the operation. Duct-to-mucosa pancreatojejunostomy was performed in group A and bundled pancreaticojejunostomy was performed in group B. The operation time, intraoperative blood loss, and pancreatic leakage of the two groups were assessed. The occurrence of pancreatic leakage after the operation in different patients was analyzed. RESULTS The differences in operative time and intraoperative bleeding between groups A and B were not significant (P > 0.05). In group A, the time of pancreatojejunostomy was 26.03 ± 4.40 min and pancreatic duct diameter was 3.90 ± 1.10 mm. These measurements were significantly higher than those in group B (P < 0.05). The differences in the occurrence of pancreatic leakage, abdominal infection, abdominal hemorrhage and gastric retention between group A and group B were not significant (P > 0.05). The rates of pancreatic leakage in patients with preoperative albumin < 30 g/L, preoperative jaundice time ≥ 8 wk, and pancreatic duct diameter < 3 mm, were 23.33%, 33.96%, and 19.01%, respectively. These were significantly higher than those in patients with preoperative albumin ≥ 30 g/L, preoperative jaundice time < 8 wk, and pancreatic duct diameter ≥ 3 cm (P < 0.05). Logistic regression analysis showed that preoperative albumin < 30 g/L, preoperative jaundice time ≥ 8 wk, and pancreatic duct diameter < 3 mm were risk factors for pancreatic leakage after PD (odds ratio = 2.038, 2.416 and 2.670, P < 0.05). CONCLUSIONS The pancreatointestinal anastomosis method during PD has no significant effect on the occurrence of pancreatic leakage. The main risk factors for pancreatic leakage include preoperative albumin, preoperative jaundice time, and pancreatic duct diameter.