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Introduction and Objectives: To study the impact of injecting intracoronary eptifibatide plus vasodilators via thrombus aspiration catheter vs thrombus aspiration alone in reducing the risk of no-reflow in acute ST-elevation myocardial infarction (STEMI) with diabetes and high thrombus burden., Methods: The study involved 413 diabetic STEMI patients with high thrombus burden, randomized to intracoronary injection (distal to the occlusion) of eptifibatide, nitroglycerin and verapamil after thrombus aspiration and prior to balloon inflation (n=206) vs thrombus aspiration alone (n=207). The primary endpoint was post procedural myocardial blush grade and corrected Thrombolysis in Myocardial Infarction (TIMI) frame count (cTFC). Major adverse cardiovascular events were reported at 6 months., Results: The intracoronary eptifibatide and vasodilators arm was superior to thrombus aspiration alone regarding myocardial blush grade-3 (82.1% vs 31.4%; P=.001). The local intracoronary eptifibatide and vasodilators arm had shorter cTFC (18.16±6.54 vs 29.64±5.53, P=.001), and better TIMI 3 flow (91.3% vs 61.65%; P=.001). Intracoronary eptifibatide and vasodilators improved ejection fraction at 6 months (55.2±8.13 vs 43±6.67; P=.005). There was no difference in the rates of major adverse cardiovascular events at 6 months., Conclusions: Among diabetic patients with STEMI and high thrombus burden, intracoronary eptifibatide plus vasodilators injection was beneficial in preventing no-reflow compared with thrombus aspiration alone. Larger studies are encouraged to investigate the benefit of this strategy in reducing the risk of adverse clinical events., (Copyright © 2021 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)