Proton pump inhibitors (PPIs) increase enteric bacterial colonization, overgrowth, and translocation, all effects which might predispose to spontaneous bacterial peritonitis. We investigated whether PPI usage is associated with spontaneous bacterial peritonitis. Our retrospective case-control study included 116 consecutive cirrhotic patients with ascites who underwent diagnostic paracentesis upon hospital admission (2002-2005). Spontaneous bacterial peritonitis was defined as paracentesis yielding >or=250 polymorphonuclear leukocytes/ml. We performed logistic regression to determine the risk of spontaneous bacterial peritonitis by PPI usage. Of the 116 subjects, 32 had spontaneous bacterial peritonitis. Patient characteristics were similar between groups with and without infection, with the exception of the Model for End-Stage Liver Disease score (median: 23 and 18, respectively; P = 0.002). Crude and adjusted odds ratios for the development of spontaneous bacterial peritonitis by exposure to PPIs were 1.22 (95% confidence interval: 0.52-2.87) and 1.05 (0.43-2.57), respectively. In conclusion, we did not find a positive association between PPI use and spontaneous bacterial peritonitis.