In-stent restenosis (ISR) is a challenging syndrome that affects drug-eluting stents and bare-metal stents. However, data comparing the outcomes of drug-eluting versus bare-metal ISR are limited. Our objective was to evaluate the long-term clinical outcomes of drug-eluting versus bare-metal ISR. Patients who underwent percutaneous coronary intervention at Cleveland Clinic for ISR from 05/1999 to 06/2007 were included. Unadjusted outcomes were tested using Kaplan-Meier curves followed by multivariable adjusted Cox proportional hazards analyses. Twenty seven variables, including type of stent used to treat ISR and procedural date, were included. The primary end point was a composite of death, myocardial infarction (MI), or target lesion revascularization (TLR). The secondary endpoints were components of the primary endpoint. Of 931 patients identified, 225 had drug-eluting ISR and 706 had bare-metal ISR. There were 279 cumulative events for a median follow-up of 3.2 years. The primary endpoint was not different between drug eluting and bare-metal ISR (22% versus 33%, adjusted hazard ratio [HR] 1.14; 95% confidence interval [CI], 0.79-1.66; P = 0.49). The secondary endpoints of death (8% versus 16%, adjusted HR 1.05; 95% CI, 0.56-1.98; P = 0.88), MI (4% versus 5%, adjusted HR 1.48; 95% CI, 0.54-4.04; P = 0.45), and TLR (15% versus 16%, adjusted HR 1.30; 95% CI, 0.81-2.11; P = 0.28) were also not different. This study represents the largest analysis comparing drug-eluting to bare-metal ISR. On multivariable Cox proportional hazard analyses, drug-eluting and bare-metal ISR have similar long term outcomes.