Background & Aims: In the past decade, there has been a growing epidemic of Clostridium difficile infection (CDI). During this time, use of proton pump inhibitors (PPIs) has increased exponentially. We evaluated the association between PPI therapy and the risk of CDI by performing a meta-analysis. Methods: We searched MEDLINE and 4 other databases for subject headings and text words related to CDI and PPI in articles published from 1990 to 2010. All observational studies that investigated the risk of CDI associated with PPI therapy and used CDI as an end point were considered eligible. Two investigators screened articles independently for inclusion criteria, data extraction, and quality assessment; disagreements were resolved based on consensus with a third investigator. Data were combined by means of a random-effects model and odds ratios were calculated. Subgroup and sensitivity analyses were performed based on study design and antibiotic use. Results: Thirty studies (25 case-control and 5 cohort) reported in 29 articles met the inclusion criteria (n = 202,965). PPI therapy increased the risk for CDI (odds ratio, 2.15, 95% confidence interval, 1.81-2.55), but there was significant heterogeneity in results among studies (P < .00001). This association remained after subgroup and sensitivity analyses, although significant heterogeneity persisted among studies. Conclusions: PPI therapy is associated with a 2-fold increase in risk for CDI. Because of the observational nature of the analyzed studies, we were not able to study the causes of this association. Further studies are needed to determine the mechanisms by which PPI therapy might increase risk for CDI. © 2012 AGA Institute.