Background Second-generation drug-eluting stents (DES) have been used widely to treat DES in-stent restenosis (ISR), which remains a clinical challenge. Knowledge of the outcomes of repeated second-generation DES implantation for focal versus nonfocal-type ISR is still missing. Methods In the current study, 254 patients with DES-ISR were divided into focal or nonfocal groups according to their ISR angiographic types. All patients with ISR lesions included in the current study received second-generation DES. Treatment modalities for both groups were similar without any systematic bias toward either group. The primary endpoint of the study was the occurrence of major adverse cardiac events (MACEs) over a 2-year follow-up period. MACEs were defined as cardiac death, myocardial infarction, and target lesion revascularization. Results The nonfocal-type group showed significantly greater incidence of MACEs than the focal-type group (38.3 vs. 24.1%; P = 0.03), in which the occurrence of target lesion revascularization was more pronounced (32.3 vs. 18.4%; P = 0.02). However, this group showed a higher incidence of type B2/C lesions (69.5 vs. 41.4%; P < 0.01), with longer lesion length, and received significantly more and longer reimplanted stents than the focal-type group. Cox regression analysis indicated that nonfocal-type ISR was an independent predictor of MACEs (odds ratio 2.134, 95% confidence interval 1.173-3.884; P = 0.014) after adjusting for all significant variables. Conclusion In the current study, second-generation DES is more effective in the treatment of focal-type DES-ISR than nonfocal-type ISR in terms of the occurrence of MACEs. Nonfocal-type ISR is an independent predictor of MACEs after the treatment of DES-ISR with second-generation DES. Copyright (C) 2015 Wolters Kluwer Health, Inc. All rights reserved.