To assess the impact of intravenous (IV) antibiotic prophylaxis on the incidence of pancreatic infection and the mortality rate in severe acute pancreatitis. Restropective review of a cohort of 180 patients with severe acute pancreatitis. A tertiary referral center in Sacramento, Calif. The use of IV antibiotic prophylaxis evolved during 3 periods from no antibiotics in 50 patients (1982-1989), to nonprotocol use in 55 patients (1990-1992), to a 4-week course of imipenem-cilastatin sodium (1993-1996) given to 75 patients having Acute Physiology and Chronic Health Evaluation (APACHE) II scores greater than 6 and pancreatic necrosis (> 15% of the gland), peripancreatic necrosis, or peripancreatic collection. Pancreatic infection and mortality. Without antibiotic prophylaxis, the incidence of pancreatic infection was 76% (38/50). Intravenous antibiotic prophylaxis reduced the infection rate of 45% (25/55) (P = .03). The imipenem-cilastatin protocol further reduced the infection rate to 27% (20/75) (P = .04). The mortality rates showed only a decreasing trend, from 16% (1982-1989) to 7% (1990-1992) to 5% (1993-1996) (P = .11). Patients with sterile severe acute pancreatitis had a mortality rate of 2% (2/97); whereas 17% (14/83) of patients with infection succumbed to the disease. Patients developing infection within the first 4 weeks from the onset of illness had mortality rates ranging from 19% to 40%, compared with 0% to 8% for those who became infected after 4 weeks. No patient with pancreatic infection developing after 4 weeks died with the imipenem-cilastatin protocol. Intravenous antibiotic prophylaxis significantly reduced the infection rate in severe acute pancreatitis, with only a trend toward improved survival. A prospective, randomized, double-blind multicenter trial comparing the efficacy of different types and/or combinations of antibiotic prophylaxis in severe acute pancreatitis is indicated.