Objective: To investigate the factors responsible for pancreatic fistula after pancreaticoduodenectomy (PD) and the prevention measures. Methods: The clinical data of 127 patients undergoing PD in our hospital between January 2009 and January 2012 were reviewed, and the potential factors for pancreatic fistula were evaluated by both univariate and multivariate analyses. Results: The incidence of post-PD pancreatic fistula was 12.6% in the entire group of the patients. Univariate analysis showed that age, preoperative total serum protein level, pancreatic tissue texture, diameter of the main pancreatic duct, operative time, intraoperative blood loss, and postoperative serum albumin level were associated with post-PD pancreatic fistula. Further, multivariate analysis revealed that age (≥ 65 years), soft pancreatic remnant and long operative time were the independent risk factors for post-PD pancreatic fistula. Conclusion: Old age, soft pancreatic remnant and prolonged operative time are independent risk factors for post-PD pancreatic fistula. A specialized surgical team, and standardized and skilled surgical performance are essential for reducing the incidence of post-PD pancreatic fistula.