To assess the safety of the pancreatic anastomosis after pancreatico-duodenectomy (PD). Non-randomized prospective trial in consecutive patients. University hospital. 171 consecutive patients with resectable periampullary cancer (80%) or intractable pain due to chronic pancreatitis (20%) undergoing PD. Pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG). Mortality and morbidity rates due to anastomotic leak following PJ and PG. 91 PJ and 80 PG patients were comparable for age, gender, total bilirubin, ASA grading, indication for PD, operating time, pancreas texture, blood loss and replacement. The rate of pancreatic fistula was significantly higher in PJ patients (13%) than in PG patients (3.7%) (12 vs. 3, p = 0.029). Overall death rate was significantly higher after PJ (12%) than after PG (3.7%) (11 vs. 3, p = 0.047). Fatal outcome due to pancreatic leak (3 vs. 1, p = 0.83) and other death rates (8 vs. 2, p = 0.14) were not significantly different in PJ and PG groups, respectively. PJ was associated with significantly higher pancreatic leak rate than PG. However, there was no statistically significant difference in mortality rates directly related to pancreatic leak.