Objectives: The aim of this pilot study was to compare intracoronary bolus-only with standard intravenous bolus plus maintenance infusion of tirofiban with respect to improvement in myocardial reperfusion after primary percutaneous coronary intervention (p-PCI). Background: Changes in clinical practice may obviate the need for a maintenance infusion of small molecule glycoprotein IIb/IIIa inhibitors in current practice. Methods: Forty-nine patients undergoing p-PCI were randomized to either intracoronary bolus-only (n = 25) or intravenous bolus plus infusion (n = 24) of tirofiban. The primary end point was coronary hemodynamic indices of microvascular perfusion measured 4–5 days after p-PCI. The secondary end points were ST segment resolution at 90 min, the corrected TIMI frame count and myocardial blush grade. At 6 months, echocardiography and technetium-99m single-photon-emission computed tomography were performed. Results: Microvascular perfusion did not differ significantly between the two treatment groups: index of microvascular resistance (27 ± 13 vs. 35 ± 15 U, P = 0.08) and coronary flow reserve (2.2 ± 0.7 vs. 1.9 ± 0.6, P = 0.25). The corrected TIMI frame counts assessed in the first (P = 0.13) and the second (P = 0.09) catheterization or the myocardial blush grades evaluated immediately (P = 0.23) and 4–5 days after MI (P = 1.00) were not significantly different between the two groups. At 6 months, there was no difference between the two groups in infarct size, left ventricular volumes, or ejection fraction. Conclusions: The standard intravenous bolus plus maintenance infusion of tirofiban in p-PCI is not superior to intracoronary bolus-only administration with respect to microvascular perfusion. Further, adequately powered randomized trials are warranted to evaluate the clinical outcomes associated with this strategy. © 2011 Wiley Periodicals, Inc.