Objective To systematically assess the efficacy and clinical significance of antibiotic prophylaxis in severe acute pancreatitis (SAP), so as to provide references for its rational clinical application. Methods For collecting the randomized controlled trials (RCTs) about antibiotic prophylaxis in SAP, a search was conducted in MEDLINE, EMbase, Cochrane Central Register of Controlled Trials, CBM and CNKI from the date of their establishment to August, 2010. After the clinical studies meeting the inclusive criteria were extracted and their quality was assessed. Meta-analysis was conduced by using RevMan 5.0 software. Results Twelve RCTs were included with a total of 777 patients. The results of Meta-analysis showed compared with the control group, the antibiotic prophylaxis group was not associated with a statistically significant reduction in mortality (RR=0.75, 95%CI 0.50 to 1.12), in the incidence of infected pancreatic necrosis (RR 0.82, 95%CI 0.63 to 1.09), in surgical interventions (RR=0.97, 95%CI 0.74 to 1.26), and in the incidence of nonpancreatic infections (RR=0.73, 95%CI 0.48 to 1.10). Conclusion Antibiotic prophylaxis for SAP does not reduce mortality, infected necrosis, or surgical intervention.