OBJECTIVE It is still unproven whether prophylactic antibiotics can reduce mortality from acute necrotizing pancreatitis (ANP). The aim of this study was to investigate whether antibiotic therapy can influence long-term outcome in ANP and how appropriate this therapy is. METHODS ANP was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptide levels were used to verify comparable disease severity. Starting 6 hours after induction, animals randomly received saline (n = 60), 20 mg/kg imipenem (n = 62), or 10 mg/kg ciprofloxacin (n = 60) every 8 hours for 7 days. On day 7, half of each group was killed so a quantitative pancreatic bacteriology could be conducted. The other half was analyzed at 21 days for long-term mortality, late bacteriologic changes, abscesses, and pseudocysts. RESULTS Comparable trypsinogen activation peptide increases confirmed equally severe ANP in each group before treatment. Imipenem and ciprofloxacin significantly reduced the number of infected pancreatic specimens, bacterial counts, and identified species at 1 week. At 3 weeks, pancreatic infection prevalence was lower in animals treated with antibiotics; abscess formation was reduced and pseudocysts were smaller and less frequently infected. Survival was significantly improved by imipenem and ciprofloxacin. CONCLUSIONS Antibiotic treatment reduces early and late septic pancreatic complications and improves survival from experimental ANP.