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BACKGROUND： Postoperative pancreatic fistula （POPF） is a serious complication and results in prolonged hospitalization and high mortality. The present study aimed to evaluate the safety and effectiveness of total closure of pancreatic section for end-to-side pancreaticojejunostomy in pancreaticoduodenectomy （PD）. METHODS： This was a prospective randomized clinical trial comparing the outcomes of PD between patients who un- derwent total closure of pancreatic section for end-to-side pancreaticojejunostomy （Group A） vs those who underwent conventional pancreaticojejunostomy （Group B）. The primary endpoint was the incidence of pancreatic fistula. Secondary endpoints were morbidity and mortality rates. RESULTS： One hundred twenty-three patients were included in this study. The POPF rate was significantly lower in Group A than that in Group B （4.8% vs 16.7%, P〈0.05）. About 38.3% patients in Group B developed one or more complications; this rate was 14.3% in Group A （P〈0.01）. The wound/abdomi- nal infection rate was also much higher in Group B than that in Group A （20.0% vs 6.3%, P〈0.05）. Furthermore, the average hospital stays of the two groups were 18 days in Group A, and 24 days in Group B, respectively （P〈0.001）. However, there was no difference in the probability of mortality, biliary leakage,delayed gastric emptying, and pulmonary infection between the two groups. CONCLUSION： Total closure of pancreatic section for end-to- side pancreaticojejunostomy is a safe and effective method for pancreaticojejunostomy in PD.