Background The importance of ischemia-guided (IG) revascularization, in which revascularization was performed in the matched coronary artery with the perfusion abnormality on myocardial perfusion image (MPI) has not been determined. Method and Results The impact of IG was evaluated in 5340 patients with multivessel coronary disease who underwent percutaneous coronary intervention (PCI) with drug-eluting stents (N=2587) or coronary artery bypass graft surgery (CABG, N=2753). MPI was performed in 42.3% of patients and IG revascularization in 17.3%, including 12.4% in PCI and 21.8% in CABG patients (P<0.001). The incidence of major adverse cardiac and cerebrovascular events (MACCE) including death, myocardial infarction (MI), stroke, or repeat revascularization was significantly lower in the IG than in the non-IG group (16.2% vs. 20.7%; adjusted hazard ratio [aHR], 0.73; 95% confidence interval [CI], 0.60 to 0.88; P=0.001), primarily driven by the lower repeat revascularization rate (9.9% vs. 22.8%; aHR, 0.66; 95% CI, 0.49 to 0.90; P=0.009). Subgroup analysis showed that IG reduced the risk of MACCE in PCI (17.4% vs. 22.8%; aHR, 0.59; 95% CI, 0.43 to 0.81; P=0.001), but not in CABG (16.0% vs. 18.5%; aHR, 0.87; 95% CI, 0.67 to 1.14; P=0.31) patients. The composite incidence of death, MI, or stroke did not differ between the IG and non-IG groups in overall (11.7% vs. 12.5%; aHR 0.84; 95% CI, 0.66 to 1.06; P=0.13), PCI, or CABG patients. Conclusion IG revascularization using MPI, particularly in PCI treated patients, appears to decrease the risk of repeat revascularization and MACCE for patients with multivessel disease.