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Cirrhosis affects millions of people around the world and is associated with increased morbidity and mortality. Spontaneous bacterial peritonitis (SBP) is a common complication of liver disease with cirrhosis and accounts for up to 30% of infections in patients with cirrhosis. Patients with a history of SBP and those deemed to be at high risk often are prescribed antibiotics to reduce the incidence of SBP. Fluoroquinolones and sulfamethoxazole-trimethoprim are commonly used antibiotics for long-term prevention for these specified populations; however, these antibiotics are associated with several adverse effects and interactions that may be harmful to patients. In addition, resistance development may decrease the efficacy of SBP treatment and prophylaxis. Given these limitations, rifaximin, a nonabsorbable, broad-spectrum antibiotic that is used for hepatic encephalopathy, may serve as a prophylactic alternative to conventional therapy. This review discusses guideline-recommended therapy and the evidence for using rifaximin for SBP prophylaxis.