Patterns of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation and outcomes after treatment have not been studied systematically in all comers. We compared patterns of ISR and outcomes of repeated percutaneous coronary intervention in consecutive patients with DES-ISR. A total of 137 patients with 182 lesions underwent repeated percutaneous coronary intervention for DES-ISR at Columbia University Medical Center from August 2004 to April 2006. DES-ISR was treated with repeated DES placement in 84% of patients and balloon angioplasty in 16%. There was 1 stent thrombosis at 30 days, and at 1 year, major adverse cardiac events occurred in 10% of patients, driven primarily by an 8% rate of target-lesion revascularization. After exclusion of 12 patients with multiple ISR lesions, data were further analyzed from 125 patients with 152 DES-ISR lesions, of which 118 were originally treated with sirolimus-eluting stents and 34 were treated with paclitaxel-eluting stents (PES-ISR). Baseline features were well matched between the 2 groups, except that patients with PES-ISR were older. A focal pattern of ISR was observed in 69.5% of patients overall. However, patients originally treated with a PES had a significantly higher frequency of diffuse-intrastent ISR in comparison with sirolimus-eluting stent ISR (30.3% vs 13.6%, p = 0.03). In conclusion, the pattern of ISR in most DES-ISR in this unselected patient population was focal, with higher rates of diffuse intrastent restenosis seen with PES-ISR. Treatment with either repeated DES implantation or balloon angioplasty for DES-ISR was safe and associated with low overall rates of target-lesion revascularization and major adverse cardiac events at 1 year.