OBJECTIVES: In patients receiving long-term low-dose aspirin for prevention of adverse cardiovascular (CV) events, proton pump inhibitors (PPIs) are often prescribed to prevent aspirin-induced gastrointestinal bleeding. However, PPIs may reduce the therapeutic efficacy of aspirin. This study investigated the effect of co-administration of PPIs in aspirin users with a first acute myocardial infarction (AMI) or stroke on the risk of recurrence of such a CV event. METHODS: A retrospective cohort study using the Clinical Practice Research Datalink (CPRD) was conducted in patients with at least one occurrence of AMI or stroke between 1998 and 2014, and who received at least one prescription of aspirin (30-325 mg/day) after the first AMI or stroke. Concomitant use of aspirin and PPIs was defined as overlaps between periods of current use of aspirin and of PPIs. The hazard ratio (HR; i.e. the instantaneous risk in concomitant use of aspirin and PPIs relative to that in aspirin use alone) was estimated using a Cox proportional hazards model with time-varying covariates. The estimate was adjusted for multiple potential confounders such as age, BMI, socioeconomic status, smoking status and history of diabetes. RESULTS: The study population consisted of 39,794 patients. During the follow-up period [range: 0.0-16.9 years; mean (SD): 4.1 (3.8) years], 18,094 patients had no prescription of PPIs, and 13,013 patients concomitantly used aspirin and PPIs for a cumulative duration longer than 50% of the cumulative duration of aspirin use.  AMI or stroke recurred in 4,307 patients, with mean (SD) time from the first to the second event being 2.6 (2.7) years. Adjusted HR (95% CI) of AMI or stroke in aspirin plus PPIs versus aspirin use was 1.23 (1.07-1.41). CONCLUSIONS: Co-administration of PPIs in aspirin users with a first AMI or stroke is associated with an increased risk of recurrence of such a CV event.