ObjectiveTo systematically review the association between use of proton pumps inhibitors (PPIs) and clostridium difficile infection (CDI), so as to provide evidence for doctors' prescription. MethodsWe electronically searched databases including PubMed, The Cochrane Library (Issue 8, 2015), Web of Science, Ovid, CBM, CNKI, VIP, WanFang Data to collect case-control studies and cohort studies about the association between use of PPIs and CDI from January 1990 to October 2015. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies. Then meta-analysis was performed using RevMan 5.3 software. ResultsA total of 47 articles involving 50 studies with 309620 cases were included. According to whether infected by clostridium difficile or not, these cases were divided into the case group (n=15913) and the control group (n=293707). The result of meta-analysis showed that the CDI rate of the PPIs therapy group was higher than that of the control group (OR=1.99, 95%CI 1.72 to 2.31, P<0.01, I2=87%) but a significant heterogeneity was found among studies. So subgroup analyses were performed according to the type of study design, type of patients, sample size and NOS scores of included studies. The results showed that, within different subgroups, the CDI rate of the PPIs therapy group was higher than that of the control group with significance, but the heterogeneity among studies was still existed. ConclusionCurrent evidence shows the use of PPI is associate with a 2-fold increase of the risk of CDI. Due to limited quality of the included studies, the above conclusion needs to be verified by more high quality studies.