OBJECTIVES: Several studies have raised concern regarding the possible association between proton-pump inhibitors (PPIs) and Clostridium difficile infection (CDI). We aimed to perform a systematic review of incident and recurrent CDI in PPI users, and to evaluate the relative impact of concurrent antibiotic use, or switching acid suppression to histamine-2-receptor antagonists (H2RAs). METHODS: We searched MEDLINE and EMBASE from inception to December 2011 for controlled observational studies that reported on the risk of CDI with and without PPI use. We performed random effects meta-analysis and assessed statistical heterogeneity using the I(2) statistic. RESULTS: We included 42 observational studies (30 case-control, 12 cohort) totalling 313,000 participants overall. Pooled analysis of 39 studies showed a statistically significant association between PPI use and risk of developing CDI, odds ratio (OR) 1.74 (95% confidence interval (CI) 1.47-2.85, P