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Background We developed a new combined strategy of thrombus aspiration plus intra-infarct-related artery (IRA) bolus administration of tirofiban via the aspiration catheter in patients with ST-segment elevation myocardial infarction (STEMI). This strategy can reduce the distal embolism and achieve highly localized concentrations of tirofiban, which can improve myocardial reperfusion without increasing the risk of bleeding. The aim of this study was to investigate whether this combined strategy is superior to thrombus aspiration alone in improving myocardial perfusion in patients with STEMI undergoing primary angioplasty.Results Baseline characteristics of the two groups were well-balanced. The TIMI 3 flow showed a better tendency in the intra-IRA group than in the aspiration alone group (97.22% vs. 87.04%, X~2=7.863, P=0.049). The peak of CK-MB (83.9 (68.9-310.5) U/L vs. 126.1 (74.7-356.7) U/L, P=0.034) and Tnl (42.7 (14.7-113.9) ng/ml vs. 72.5 (59.8-135.3) ng/ml, FMD.029) were lower in the intra-IRA group than in the aspiration alone group. LVEF in the hospital favored the intra-IRA group, (45.7±8.3)% to (42.9±12.1)%, t=1.98, P=0.049. There was a tendency towards a lower MACE at 9-month follow-up in the intra-IRA group although it did not reach statistical difference (Log-rank X~2=2.865, P=0.09). There was no statistical difference in any bleeding events between the two groups.Conclusions Thrombus aspiration plus intra-IRA bolus administration of tirofiban combined with angioplasty may be related with improved myocardium perfusion, saved more myocardium, and resulted in a better clinical prognosis.