ABSTRACT: Although the angiographic rates of in-stent restenosis (ISR) at later months have reduced dramatically with the introduction of drug-eluting stents (DESs), some patients with ISR after implantation of DES present with acute coronary syndrome (ACS). Here, we sought to identify parameters influencing the likelihood of restenosis with ACS presentation after DES implantation. Stented patients (n=3,817) with DESs in the Korea University Anam Hospital percutaneous coronary intervention registry were reviewed retrospectively for inclusion. In this database, 247 age- and sex-matched patients (6.5%) with ISR were allocated to either the Stable ISR group (n=78) or the ACS ISR group (n=73). Predictors of in-stent restenosis were identified with Cox regression analyses. Age (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.02 to 1.27; p=0.026), diabetes (HR, 8.40; 95% CI, 1.30 to 54.1; p=0.025), use of aspirin (HR, 0.003; 95% CI, 0.0001 to 0.63; p=0.03), clopidogrel (HR, 0.005; 95% CI, 0.001 to 0.121; p=0.001), renin-angiotensin system (RAS) blocker (HR, 0.02; 95% CI, 0.003 to 0.14; p<0.001), use of first -generation DES (HR, 0.07; 95% CI, 0.009 to 0.59; p=0.014), and matrix metalloproteinase 2 (MMP-2) levels (HR, 1.120; 95% CI, 1.001 to 1.190; p=0.004) during follow-up angiograms were significant predictors of ISR with ACS presentation during the 3 year follow-up. Age, diabetes, the use of first generation DES, and increased MMP-2 levels were significant predictors of ISR with ACS presentation; moreover, the use of aspirin, clopidogrel, RAS blocker, and the use of second generation DESs prevented ISR with ACS presentation.