Large thrombus burden (LTB) lesions in the context of primary percutaneous coronary intervention (p-PCI) have been related to unsuccessful angiographic reperfusion and unfavorable clinical outcomes. However, the hazard of LTB treatment on myocardial damage has not been evaluated. We investigated the impact of LTB on myocardial damage using contrast-enhanced cardiac magnetic resonance (CE-CMR) in the setting of p-PCI. In 327 patients, who underwent p-PCI without thrombus aspiration within 12 hours from symptom onset, we prospectively assessed the impact of LTB on infarct size and microvascular damage using CE-CMR. LTB was defined by the presence of Thrombolysis In Myocardial Infarction thrombus score ≥3 in patent infarct-related artery (IRA); or by "cut-off" occlusion pattern and/or large reference vessel diameter (≥3.5 mm) in occluded IRA. One hundred ninety-seven patients (60.2%) showed LTB and 130 (39.8%) did not. Distal embolization occurred in 18.8% patients with versus 6.9% without LTB (p = 0.003). At CE-CMR, patients with LTB had larger infarct size index (27.5 ± 11.1 vs 22.1 ± 17.5, p = 0.009) and more often transmural necrosis (70.5% vs 55.4%, p = 0.008) compared with patients without LTB. Excluding patients with distal embolization, patients with LTB still had larger necrosis. At multivariate analysis, occluded (IRA) at baseline, anterior infarction, and presence of LTB predicted transmural necrosis. In conclusion, LTB in the setting of p-PCI is related to larger myocardial damage as detected by CE-CMR, regardless of angiographic detectable distal embolization.