Background: Infectious complications are the main cause of late death in patients with acute pancreatitis. Routine prophylactic antibiotic use following a severe attack has been proposed but remains controversial. On the other hand, nutritional support has recently yielded promising clinical results. The aim of study was to compare enteral vs. parenteral feeding for prevention of infectious complications in patients with predicted severe acute pancreatitis. Methods: We screened 466 consecutive patients with acute pancreatitis. A total of 70 patients with objectively graded severe acute pancreatitis were randomly allocated to receive either total enteral nutrition (TEN) or total parenteral nutrition (TPN), within 72 h of onset of symptoms. Baseline characteristics were well matched in the two groups. Results: The incidence of pancreatic infectious complications (infected pancreatic necrosis, pancreatic abscess) was significantly lower in the enterally fed group (7 vs. 16, p = 0.02). In the TEN group, 7 patients developed multiple organ failure whereas 17 parenterally fed patients developed multiple organ failure (p = 0.02). Overall mortality was 20% with two deaths in the TEN group and twelve in the TPN group (p < 0.01). Conclusion: Early TEN could be used as prophylactic therapy for infected pancreatic necrosis since it significantly decreased the incidence of pancreatic infectious complications as well as the frequency of multiple organ failure and mortality.