Objectives. The aim of our study was to investigate the predictors of target lesion revascularization (TLR) and to compare the in-stent restenosis (ISR) progression rates of different 2nd-generation drug-eluting stents (DES). Background. The predictors of early and late TLR after 2nd-generation DES implantation have not been fully evaluated. Methods. We analyzed 944 stented lesions from 394 patients who had at least two serial follow-up angiograms, using quantitative coronary angiography (QCA) analysis. The study endpoints were TLR and the velocity of diameter stenosis (DS) progression. Results. TLR occurred in 58 lesions (6.1%) during the first angiographic follow-up period and 23 de novo lesions (2.4%) during the following second interval. Independent predictors for early TLR were diabetes mellitus (DM) (HR 2.58, 95% CI 1.29–5.15, p=0.007), previous percutaneous coronary intervention (PCI) (HR 2.41, 95% CI 1.03–5.65, p=0.043), and postprocedure DS% (HR 1.08, 95% CI 1.05–1.11, p<0.001, per 1%), while predictors of late TLR were previous PCI (HR 9.43, 95% CI 2.58-34.52, p=0.001) and serum C-reactive protein (CRP) (HR 1.60, 95% CI 1.28-2.00, p<0.001). The ISR progression velocity (by DS%) was 12.1 ±21.0%/year and 3.7 ±10.1%/year during the first and second follow-up periods, respectively, which had no significant difference (p>0.05) between the four types of DESs. Conclusions. Our data showed that predictors for TLR may be different at different time intervals. DM, pervious PCI, and postprocedure DS could predict early TLR, while previous PCI and CRP level could predict late TLR. Contemporary DESs had similar rates of ISR progression rates. Trial Registration. This study was retrospectively registered and approved by the institutional review board of Seoul National University Hospital (no. 1801–138-918).