Despite the established clinical efficacy following intravascular imaging (IVI)-guided percutaneous coronary intervention (PCI) than angiography-guided PCI, evidence regarding prognostic benefits of IVI-guided PCI in acute myocardial infarction (AMI) patients with high thrombus burden remains limited. Using the nationwide registries of KAMIR-NIH and KAMIR-V, we evaluated the prognostic impact of IVI-guided PCI in AMI patients with high thrombus burden. A total of 4,074 patients with AMI and TIMI thrombus grades 4 or 5 who underwent aspiration thrombectomy were selected, of whom 892 patients (21.9%) received IVI-guided PCI and 3,182 patients (78.1%) received angiography-guided PCI. Primary outcome was major adverse cardiovascular event (MACE, a composite of all-cause death, MI, repeat revascularization, and stent thrombosis). Major secondary efficacy outcome was cardiac death and safety outcome was stroke at 3 years. During the median 3 years of follow-up, the risk of MACE was significantly lower in the IVI-guided PCI group than in the angiography-guided PCI group (12.9% vs 16.3%; adjusted HR, 0.80; 95% CI, 0.65 to 0.98; p = 0.035), mainly driven by a lower risk of all-cause death (5.7% vs 10.0%; adjusted HR, 0.65; 95% CI, 0.48 to 0.89; p = 0.007). IVI-guided PCI also showed lower risk of cardiac death compared with angiography-guided PCI (3.8% vs 7.0%; adjusted HR, 0.65; 95% CI, 0.44 to 0.95; p = 0.025). There was no significant difference in the risk of stroke between the groups. In this hypothesis generating study, IVI-guided PCI was associated with a lower risk of MACE and cardiac death than angiography-guided PCI in AMI patients with high thrombus burden.