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Background: Pharmacokinetic and prior interaction studies on thienopyridine-proton pump inhibitors (PPI) provide conflicting data for cardiovascular outcomes. There is no established evidence on the association of concomitant use of PPI-thienopyridine with adverse cerebrovascular outcomes.Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) and cohort studies from inception to December 2016, reporting following outcomes among patients treated with thienopyridine + PPI vs. thienopyridine alone: 1. ischemic stroke (IS), 2. combined ischemic and hemorrhagic stroke, 3. composite outcome of stroke, myocardial infarction (MI) and cardiovascular (CV) death, 4. MI, 5. all-cause mortality, and 6. major or minor bleeding events. We performed subgroup analyses to assess IS recurrence rates for eligible studies, and assess outcomes amongst the two study designs. We calculated pooled relative risk (RR) ratios and 95% CI using random-effects models.Results: We identified 22 studies (12 RCTs and 10 cohort studies) with 131,714 participants. Concomitant use of PPI and thienopyridines was associated with increased risk of IS [RR=1.75 (95%CI: 1.41-2.16), I2=0%], composite stroke/MI/CV death [RR=1.14 (95%CI 1.01-1.29), I2=74%], and MI [RR=1.19 (95%CI: 1.0-1.4), I2=80%]. The co-administration of PPI and thienopyridines was not associated with the risk of combined ischemic and hemorrhagic stroke, cardiovascular death, major or minor bleeding, and all-cause mortality. Subgroup analyses demonstrated increased risk of IS [RR=1.6 (95%CI: 1.1-2.3), I2=33%] and combined ischemic and hemorrhagic stroke [RR=1.34 (95%CI: 1.1-1.63), I2=0%] in cohort studies, while RCTs demonstrated significant risk for composite stroke/MI/CV death [RR=1.17 (95%CI: 1.04-1.32), I2=72%]. PPI-thienopyridine co-prescription did not increase the risk of stroke recurrence in patients with prior IS.Conclusions: PPI-thienopyridine co-prescription increases the risk of IS and composite stroke/MI/CV death. Our findings highlight the need for pharmacovigilance and corroborate with current guidelines for PPI deprescription, especially in patients treated with thienopyridines for the prevention of cerebrovascular events.