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Background and Aim: The use of prophylactic antibiotics to prevent infection and reduce mortality in patients with acute necrotizing pancreatitis (ANP) remains controversial. The aim of this study is to perform a systematic review of the data from randomized controlled trials to compare prophylactic antibiotic treatment of patients with ANP versus placebo. Methods: A computerized literature search was conducted using Medline, PubMed, EMBase and Cochrane Central Register of Controlled Trials (CENTRAL) for relevant articles published in English from January 1990 to March 2010. MeSH terms and keywords used to identify articles included 'antibiotic', 'pancreatitis', and 'randomized'. Outcome measures were infected pancreatic necrosis (IPN), mortality, nonpancreatic infection (NPN) and need for surgical intervention. Results: Nine trials involving 564 patients were included. Analysis suggested that IPN was significantly reduced by treatment with antibiotics (RR 0.73, 95% CI 0.54-0.98, p = 0.04). Mortality (p = 0.1), NPN (p = 0.07), and need for surgical intervention (p = 0.17) were not significantly reduced by antibiotic treatment. Subsequent subgroup analysis confirmed that antibiotics were statistically superior to controls in reducing of infected necrosis (p = 0.003) and also mortality (p = 0.02) in single-blinded randomized controlled trials. Conclusion: Prophylactic antibiotic treatment reduced occurrence of IPN, but did not affect mortality, NPN, or surgical intervention in patients with ANP. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]