Background and Aim: Proton pump inhibitors (PPI) and H2-receptor antagonists (H2RA) are frequently prescribed in hospitalized patients with cirrhosis. There are conflicting reports regarding the role of acid-suppressive therapy in predisposing hospitalized patients with cirrhosis to spontaneous bacterial peritonitis (SBP). The aim of this meta-analysis was to evaluate the association between acid-suppressive therapy and the risk of SBP in hospitalized patients with cirrhosis. Methods: We searched MEDLINE and four other databases for subject headings and text words related to SBP and acid-suppressive therapy. All observational studies that investigated the risk of SBP associated with PPI/H2RA therapy and utilized SBP as an endpoint were considered eligible. Data from the identified studies were combined by means of a random-effects model and odds ratios (ORs) were calculated. Results: Eight studies (n=3815 patients) met inclusion criteria. The risk of hospitalized cirrhotic patients developing SBP increased when using acid-suppressive therapy. The risk was greater with PPI therapy (n=3815; OR 3.15, 95% confidence interval 2.09-4.74) as compared to those on H2RA therapy (n=562; OR 1.71, 95% confidence interval 0.97-3.01). Conclusions: Pharmacologic acid suppression was associated with a greater risk of SBP in hospitalized patients with cirrhosis. Cirrhotic patients receiving a PPI have approximately three times the risk of developing SBP compared with those not receiving this medication. Prospective studies may help clarify this relationship and shed light on the mechanism(s) by which acid-suppressive therapy increases the risk of SBP in hospitalized patients with cirrhosis. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.