Aims Limited data exist regarding the impact of multi-vessel revascularization on the clinical outcomes in patients with multi-vessel disease (MVD) in drug-eluting stents (DES) era. We sought to compare long-term outcomes for single vessel revascularization (SVR) versus multi-vessel revascularization (MVR) with DES in patients with non ST-elevation acute coronary syndrome (NSTE-ACS) and MVD. Methods We studied 168 patients underwent SVR and 203 underwent MVR for NSTE-ACS and MVD from Samsung medical center percutaneous coronary intervention (PCI) database registry between April 2003 and December 2006. Major adverse cardiac events (MACE) were defined as death, myocardial infarction, or any revascularization. We calculated the Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) lesion score to assess the amount of myocardium at risk. Results Compared with patients who underwent SVR, those who underwent MVR had a higher prevalence of left main disease and usage of intravascular ultrasound (IVUS) and zotarolimus-eluting or mixed stent. Other baseline clinical, angiographic, and procedural characteristics were not significantly different between both groups, including the APPROACH score. In multivariate analysis, MVR was associated with a lower incidence of MACEs (HR 0.58; 95% CI 0.34-0.99; P<0.05) and revascularization (HR 0.46; 95% CI 0.25-0.84; P<0.05), but not of death (HR 1.04; 95% CI 0.39-2.79; P=0.93) and MI (HR 0.59; 95% CI 0.16-2.11; P=0.42). Revascularization in SVR was performed to treat lesions initially left untreated (MVR versus SVR, HR 0.99; 95% CI 0.50-1.95; P=0.97 for TVR and HR 0.20; 95% CI 0.08-0.48; P<0.001 for non-TVR). Periprocedural MI occurred more frequently in the MVR group than the SVR group (10.6% versus 3.6%, P=0.01). Stent thrombosis rate was similar in 2 groups (1.8% versus 2.9%, P=0.74). Conclusions MVR in patients with NSTE-ACS treated with DES was associated with a lower MACE rates, mainly due to reduction of revascularization. Key words: Multivessel disease • Revascularization • Drug-eluting stents