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Background The primary and secondary prevention of spontaneous bacterial peritonitis ( SBP) is recommended in high-risk patients with cirrhosis. Several studies evaluating the efficacy of rifaximin for SBP prophylaxis have yielded conflicting results. Rifaximin has the potential advantage of preventing bacterial overgrowth and translocation without the systemic side effects of broad-spectrum antibiotics. Aim To evaluate the efficacy of rifaximin in the primary and secondary prevention of SBP. Methods A literature search using five databases was performed to identify studies on the association between rifaximin and SBP. We performed two meta-analyses: (1) rifaximin compared to systemic antibiotics and (2) rifaximin compared to no antibiotics. Random-effect modelling was conducted to determine overall pooled estimates and 95% confidence intervals ( CIs). Results Five studies with 555 patients (295 rifaximin, 260 systemic antibiotics) compared rifaximin with systemic antibiotics. The pooled odds ratio ( OR) for SBP was 0.45 (95% CI 0.16-1.27; P = .13) in patients receiving rifaximin and strengthened on sensitivity analysis ( OR 0.38, 95% CI 0.19-0.76, P = .01). In the analysis comparing rifaximin with no antibiotics, there were five studies with 784 patients (186 rifaximin, 598 no antibiotics). The OR for SBP was 0.34 (95% CI 0.11-0.99; P < .05) in patients receiving rifaximin. In subgroup analysis, rifaximin reduced the risk of SBP by 47% compared to no antibiotics for primary prophylaxis and by 74% compared to systemic antibiotics for secondary prophylaxis. Conclusion Rifaximin may be effective in preventing SBP in patients with cirrhosis and ascites compared to systemically absorbed antibiotics and compared to placebo. [ABSTRACT FROM AUTHOR]