Objective: This study was conducted to compare the risk of recurrent hospitalization for major gastrointestinal (GI) complications (peptic ulcer, bleeding, and perforation) in patients at high GI risk who require ongoing antiplatelet therapy (aspirin [acetylsalicylic acid] or clopidogrel) with or without proton pump inhibitors (PPIs). Methods: This population-based, retrospective cohort study employed data from the Taiwanese National Health Insurance database (January 2001 through December 2006) for patients who had a history of hospitalization for GI complications before the initiation of antiplatelet therapy with aspirin or clopidogrel. Recurrent hospitalizations for major GI complications were analyzed using a Cox proportional hazards model, with adjustment for age, sex, ulcer-related medical history, ulcer-related risk factors, and use of ulcer-related medications during follow-up. The propensity score method was applied to adjust for selection bias. Results: The analysis included data from 14,627 patients (12,001 receiving aspirin, 2626 receiving clopidogrel). The incidence of recurrent hospitalization for major GI complications was 0.125 per person-year in aspirin users, 0.103 per person-year in users of aspirin plus a PPI, 0.128 per person-year in clopidogrel users, and 0.152 per person-year in users of clopidogrel plus a PPI. Among aspirin users, those taking PPIs had a significantly lower adjusted risk of hospitalization for major GI complications than did non-PPI users (hazard ratio [HR] = 0.76; 95% CI, 0.64-0.91). Use of a PPI was not associated with a significant risk reduction among clopidogrel users (HR = 1.08; 95% CI, 0.89-1.33). An adjusted survival curve for the risk of recurrent hospitalization for major GI complications indicated that the risk increased numerically faster in clopidogrel users compared with those using aspirin plus a PPI, although the mean drug cost per personyear was 5.08 times higher in clopidogrel users than in users of aspirin plus a PPI. Conclusions: In this analysis in patients at high GI risk who were receiving antiplatelet therapy for the secondary prevention of cardiovascular events, aspirin plus a PPI was associated with a reduced risk of recurrent hospitalization for major GI complications. This was not the case for clopidogrel plus a PPI.