Aim To observe whether a combined thrombus burden reduction therapy during primary percutaneous coronary intervention (PCI), could improve microcirculation and enhance cardiac function in the long-term.Methods Anterior wall ST-elevation myocardial infarction(STEMI) patients with high thrombus burden were randomly assigned to receive a combined thrombus burden reduction therapy or thrombus aspiration alone. The combination of thrombus aspiration, intracoronary injection with 100 thousand units of urokinase, 5 mL tirofiban, and 200 μg nitroglycerin was performed in the experimental group, the control group was treated with thrombus aspiration. The primary end points included the percentage of patients with TIMI myocardial perfusion grade(TMPG) 3, ST segment resolution(STR) above 70%, the index of microcirculatory resistance (IMR) and left ventricular ejection fraction (LVEF) difference. The compound end points were heart failure, recurrent angina, recurrent myocardial infarction and sudden cardiac death as secondary end points. And it used bleeding academic research consortium(BARC) to define bleeding as the security point. Results 22 patients in the combined interventional group and 24 in the control group completed 1-year follow-up. The percentages of patients with TMPG 3 (68.2% vs 33.3%, P=0.006) and STR above 70% (63.6% vs 25.0%, P=0.016) were significantly higher in the combined group. IMR was significantly lower in the combined interventional group ((31.50±13.39) U vs (62.72±22.80) U, P=0.002). At 3 months and 1 year, the overall LVEF value was better in the combined interventional group (42.1% vs 40.0%, P=0.049; 41.9 % vs 39.8 %, P=0.042), respectively. At secondary end points, there were no significant difference in heart failure, recurrent angina, recurrent myocardial infarction and sudden cardiac death. There was no significant difference in bleeding between the two groups defined by BARC. Conclusion A combined thrombus burden reduction therapy during primary PCI can safely reduce thrombus burden, improve myocardial tissue perfusion, and improve cardiac function among STEMI patients with high thrombus burden.