Background: Treating in-stent restenosis (ISR) has become one of the major challenges for the interventional cardiologist. The aims of this study were to determine the feasibility and safety of treating ISR with drug-eluting stents (DES) and to determine the effect of this stents on prevention of recurrent restenosis. Methods: Eighty patients (60.9짹6.4 years old, male : female = 63 : 17) with 82 ISR lesions, who were treated successfully with DES (sirolimus- and paclitaxel-eluting stents), were enrolled. Five patients received 2 stents (1.1짹0.3 stents per lesion). In-hospital events, 30 days, and 6-month major adverse cardiac events (MACE) and angiographic data were analyzed. Results: At the time of DES implantation, number of ISR was 1.4짹0.9 and patterns of ISR by Mehran classification were type IB in 9 (10.5%), IC in 3 (3.7%), ID in 6 (7.3%), II in 19 (23.2%), III in 30 (36.7%), and IV in 15 (18.3%) lesions. Mean stent length was 27.1짹5.6 mm and acute gain was 2.58짹0.67 mm. No in-hospital events or 30 day MACE were observed. Twenty one patients with 22 lesions underwent 6-month angiographic and clinical follow-up. The late loss at 6 months was 0.13짹0.20 mm. Binary restenosis rate was 4.5% (1/22 lesion). One patient showed type IV ISR at 6 months and treated with plain old balloon angioplasty successfully. Conclusion: DES was a safe and effective method for the treatment of ISR.