Objective: To investigate the incidence of major postoperative complications after pancreatoduodenectomy (PD) and their prevention and control measures. Methods: The incidence of postoperative complications in 442 cases undergoing PD from August 1994 to December 2010 in our hospital was retrospectively studied. The cases were grouped according to different historical periods and different types of pancreatic-enteric anastomosis performed. Thirty-two cases undergoing pancreatic-enteric anastomosis by the invagination method before December 1998 were designated as group A, 305 cases undergoing end-to-side duct-to-mucosa pancreatojejunostomy after that time were assigned as group B, and 105 cases with binding invagination anastomosis were group C. The direct or indirect operation-related postoperative complications and mortality of each group were analyzed. Results: The total incidence of complications and mortality of the whole group was 29.9% and 2.3%, respectively. Comparison among the three groups showed that all the studied postoperative parameters of groups B and C were better than those of group A (all P<0.01), but the differences between group B and C had no statistical significance (all P>0.05). The incidence of direct operation related complications of group A, B and C was 43.8%, 6.6% and 6.7% (in which the incidence of pancreatic fistula was 28.1%, 3.6% and 2.9%), while the incidence of indirect operation related complications was 59.4%, 17.0% and 19.0% and the mortality rate was 21.9%, 0.7% and 1.0%, respectively. Conclusion: The prevalence of postoperative pancreatic fistula is related to the pancreaticojejunal anastomosis procedure. Expert surgical skill, meticulous technique of anastomosis and enhanced pre- and postoperative control measures are important factors for reducing complications and mortality after PD.