Use of proton pump inhibitor (PPI) reduces the risk of gastrointestinal (GI) bleeding, and is generally recommended for high GI risk patients taking nonsteroidal anti-inflammatory agents. Aspirin and/or anticoagulants have been identified as increasing the risk of GI bleeding, whereby use of PPI could reduce this risk. The use of PPI in routine practice is not well defined, especially in patients with acute coronary syndromes (ACS) who require one or several antithrombotic drugs. We analyzed the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction (PROVE IT-TIMI) 22 trial database, which enrolled patients who had been hospitalized for ACS. Patients were to be treated with aspirin, and received clopidogrel and/or warfarin at the discretion of the treating physician. We analyzed the use of PPI at baseline, which was not specified in the protocol, according to prior known GI risk factors. Of the 4162 patients enrolled, 781 (18.8%) received PPI during the course of this study. The use ranged from 14% to 67% across the number of GI risk factors of 0 to > or =4 (P < 0.0001). Individual factors most associated with increased use of PPI were a prior GI event (RR = 2.3, P < 0.001) and use of anticoagulants (RR = 1.49, P < 0.001), but not dual antiplatelet therapy. Use of PPI following ACS is modest, although it did increase with an increasing number of previously identified GI risk factors. Further, larger studies are warranted to validate prior, or identify new, risk factors as predictors of long-term bleeding, and improve awareness of GI bleeding risk such that use of PPI could be optimized.