Background: Concomitant use of antiplatelet agents and proton-pump inhibitors (PPIs) has been recommended in patients with a history of gastrointestinal (GI) hemorrhage. However, recent studies have reported that PPIs may alter clopidogrel's pharmacokinetics and potentially lead to an increased risk of recurrent adverse cardiovascular (CV) events. Methods: Using Taiwan's 2000-2006 National Health Insurance database, this population-based retrospective cohort study assessed CV and GI events in patients who had a prior history of GI bleeding and had been prescribed ongoing antiplatelet therapy after acute coronary syndrome (ACS) discharge. We identified 3,580 ACS patients and categorized them into (1) those taking clopidogrel alone, (2) those taking clopidogrel plus PPIs, and (3) those taking aspirin plus PPIs. Cox proportional hazards models were used to assess the association between the use of antiplatelet therapies and CV/GI events. Results: The clopidogrel only group and the clopidogrel plus PPI group were found to be at lower risk for GI events than the aspirin plus PPI group [adjusted hazard ratio (HR) 0.23 (95% confidence interval; CI 0.14-0.36) and HR 0.70 (0.52-0.96), respectively]. However, while the clopidogrel only group had a lower risk of CV events than the aspirin plus PPI group [HR 0.57 (0.38-0.84)], the clopidogrel plus PPI group had a significantly higher CV risk than the aspirin plus PPI group [HR 1.59 (1.18-2.13)]. Conclusions: Our findings suggest that although the use of clopidogrel plus PPIs provides GI benefits, with this treatment, there is an increased CV risk among patients with a history of GI bleeding.