Drug-eluting stent (DES) implantation is the standard treatment for patients with bare-metal stent (BMS) in-stent restenosis (ISR) and is associated with low rates of target-vessel revascularization. Outcomes in patients with DES ISR treated using repeated DES placement are less certain. A total of 119 patients who presented with BMS ISR and 119 patients with DES ISR matched for baseline characteristics were evaluated. Both groups of patients were treated using DESs and compared with regard to major adverse cardiac events, including death, myocardial infarction, and target-vessel revascularization, at 1 year. Baseline characteristics were similar between groups. Compared with patients with BMS ISR, those with DES ISR had similar 1-year rates of death (5.1% BMS ISR vs 3.5% DES ISR; p = 0.75) and myocardial infarction (2.6% BMS ISR vs 3.5% DES ISR; p = 0.72) when treated using DESs. However, at 1 year, patients with DES ISR experienced significantly higher rates of target-vessel revascularization (10.3% BMS ISR vs 22.2% DES ISR; p = 0.01), with a trend toward increased overall major adverse cardiac events, including death, myocardial infarction, and target-vessel revascularization (16.0% BMS ISR vs 25.2% DES ISR; p = 0.08). Stent thrombosis occurred with similar frequency in both groups (2.5% BMS ISR vs 0.8% DES ISR; p = 0.62). In conclusion, DES ISR continues to be a therapeutic challenge because patients with DES ISR treated using DESs experience higher rates of recurrence compared with patients with BMS ISR treated using DESs. The optimal treatment of patients with DES restenosis remains to be defined.