Background: The presence of intracoronary large thrombus burden (LTB) in the infarct-related artery increases the risk of distal embolization and no-reflow during percutaneous coronary intervention (PCI). Evaluation of whether the distal protection (DP) during primary PCI reduces adverse effects of LTB on myocardial reperfusion and infarct size was investigated. Methods and Results: A consecutive series of 88 patients with acute myocardial infarction undergoing primary PCI using DP were compared with 81 consecutive patients treated by primary PCI alone. The DP use showed similar post-procedural myocardial blush grade (MBG)-3 and infarct size, but improved corrected thrombolysis in myocardial infarction frame count (cTFC) (29±11 vs 35±20, p=0.011) and the incidence of ST-segment resolution (80.7% vs 66.7%, p=0.038). In patients with LTB present, however, the DP use reduced occurrences of no-reflow (0% vs 11.8%, p=0.036) and distal embolization (4.8% vs 17.6%, p=0.129), resulting in higher occurrences of MBG-3 (61.9% vs 35.3%, p=0.021) and ST-segment resolution (78.6% vs 50.0%, p=0.009), lower cTFC values (30±8 vs 40±22, p=0.012) and smaller infarct size (12.2±11.2 vs 18.7±11.1, p=0.015). Conclusions: With an improved myocardial reperfusion and smaller infarct size in patients with LTB, the DP during primary PCI might be a better strategy in this particular setting compared with conventional strategy.