Infectious complications currently account for 80% of deaths from acute pancreatitis. The aim of this study was to evaluate the necessity for prophylactic antibiotics in patients with severe acute pancreatitis. Twenty-three consecutive patients suffering from acute alcoholic pancreatitis with computed tomography demonstrating two or more fluid collections were randomly assigned to one of two groups receiving either nonantibiotic treatment or prophylactic antibiotics (ceftazidime, amikacine, and metronidazole for 10 days). Sepsis was always diagnosed by positive cultures. Seven episodes of severe sepsis occurred (pancreatic infection and septic shock) in the nonantibiotic group, and no infection occurred in the prophylactic antibiotic group (p < 0.03). In conclusion, the use of prophylactic antibiotics in severe alcoholic acute pancreatitis significantly reduces the incidence of severe infection.