OBJECTIVES: Following a FDA warning in November 2009, significant controversy exists regarding the outcomes of patients co-medicated with clopidogrel and omeprazole after acute coronary syndrome (ACS). This study examined the effect of proton pump inhibitors (PPI) –clopidogrel interactions on subsequent ACS emergency department and inpatient visits.   METHODS: This was a retrospective cohort study of administrative claims data for a large nationally dispersed group of commercially insured subjects between 2001 and 2008. Subjects age >18 years with a diagnosis of ACS and at least one clopidogrel prescription within 90 days after the diagnosis were included.  The clopidogrel plus PPI (C+PPI) group was defined as subjects with a minimum of 7 days overlap between the PPI and clopidogrel prescriptions.  Subjects were followed from their first clopidogrel prescription until they experienced a re-hospitalization or ER visit due to ACS, disenrolled or reached the study end. C+PPI group was matched 1:1 with clopidogrel group using propensity scoring methods with calipers. Cox proportional hazards regression was used to estimate the relative risk of an adverse cardiovascular event. RESULTS: Of the 10,101 patients taking clopidogrel, 16.98% (n=1,716) were prescribed a PPI. Propensity matching resulted in 1,697 patient pairs. The mean age was 61.50 years with a mean follow up of 259 days and 69.64% were males. 13.20% (n=224) had an ACS-related re-hospitalization or ER visit in the clopidogrel group versus 16.32% (n=277) in the C+PPI group. C+PPI use was not associated with a significantly increased risk of adverse outcomes (HR=1.221; 95% CI, 0.984-1.517) compared to clopidogrel users not co-medicated with a PPI. CONCLUSIONS: Concurrent use of clopidogrel and PPIs trended toward a non-significant increase in risk of adverse cardiovascular outcomes for ACS patients, which suggests caution may be warranted when prescribing a PPI with clopidogrel. Future studies should account for time dependence of exposure.