Background-Eptifibatide, a small-molecule glycoprotein IIb/IIIa inhibitor, is conventionally administered as a bolus plus infusion. A growing number of clinicians are using a strategy of catheterization laboratory-only eptifibatide (an off-label use) as procedural pharmacotherapy for patients undergoing percutaneous coronary intervention although the comparative effectiveness of this approach is unknown. Methods and Results-We compared the in-hospital outcome of patients undergoing percutaneous coronary intervention across 47 hospitals and treated with eptifibatide bolus plus infusion with those treated with a catheterization laboratory-only regimen. We used optimal matching to link the use of catheterization laboratory-only eptifibatide with clinical outcomes, including mortality, myocardial infarction, bleeding, and need for transfusion. Of the 84 678 percutaneous coronary interventions performed during 2010 to 2011, and meeting our inclusion criteria, eptifibatide was administered to 21 296 patients. Of these, a catheterization laboratory-only regimen was used in 4511 patients, whereas 16 785 patients were treated with bolus plus infusion. In the optimally matched analysis, compared with bolus plus infusion, a catheterization laboratory-only regimen was associated with a reduction in bleeding (optimally matched adjusted odds ratio, 0.74; 95% confidence interval, 0.58-0.93; P=0.014) and need for transfusion (optimally matched adjusted odds ratio, 0.70; 95% confidence interval, 0.52-0.92; P=0.012), with no difference in mortality or myocardial infarction. Conclusions-A catheterization laboratory-only eptifibatide regimen is commonly used in clinical practice and is associated with a significant reduction in bleeding complications in patients undergoing contemporary percutaneous coronary intervention.