Background: Clopidogrel's anti-platelet effects may be attenuated by a pharmacokinetic interaction with co-prescribed proton pump inhibitors, which inhibit oxidative pathways that convert clopidogrel into its active metabolites. Despite this, the impact of PPIs on cardiovascular risk in the absence of clopidogrel is not well defined. Aim: To report on a systematic review and meta-analysis of the association between PPIs and cardiovascular risk, independent of clopidogrel. Methods: The databases of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and ClinicalTrials.gov were systematically searched in October 2017. The primary outcome was association between PPI monotherapy and any adverse cardiovascular event. The secondary outcome was association between proton pump inhibitor monotherapy and acute myocardial infarction. Studies were excluded if they reported or did not adjust for concomitant anti-platelet therapy or involved participants aged less than 18 years. Results: A total of 22 studies were included in the systematic review. Data from 16 studies were included in the meta-analysis (involving 447 408 participants). Of these, eight were randomised controlled trials, seven were observational studies and one was a retrospective analysis of a randomised controlled trial. An increased risk of any adverse cardiovascular event with PPI monotherapy was observed using pooled data from observational studies (risk ratio 1.25, 95% CI 1.11-1.42, I2 81%, P < 0.001), but not from randomised controlled trials (risk ratio 0.89, 95% CI 0.34-2.33, I2 0%, P = 0.85). Conclusion: There is no clear evidence of an association between PPI monotherapy and increased cardiovascular risk.