Despite significant decreases in restenosis and repeated intervention achieved using drug-eluting stents (DESs), the benefit has not been homogenous across all patient and lesion subsets. Identification of correlates of DES restenosis may allow a differing management approach and lead to improved patient outcomes. The study population consisted of 3,535 consecutive patients (5,046 lesions) who underwent successful sirolimus- or paclitaxel-eluting stent implantation for >or=1 native coronary artery or bypass graft lesion from April 2003 to September 2006. From this cohort, 197 patients (237 lesions) were identified to have in-stent restenosis (ISR) requiring revascularization within 12 months of stent implantation. This group was compared with the remainder of the patient population. Logistic regression analysis was performed to identify independent predictors of DES ISR. Independent correlates of DES ISR using multivariate analysis included both clinical and procedural factors. Clinical predictors were age, hypertension, and unstable angina. Procedural predictors were left anterior descending artery intervention, number of stents implanted, stented length/lesion, and lack of intravascular ultrasound guidance. Implantation of >or=3 stents was associated with a significantly higher restenosis risk (9.7% vs 5.1%; p=0.0003). A 10-mm increase in stented length was associated with an adjusted odds ratio of 1.18 (95% confidence interval 1.03 to 1.35). Diabetes, stent diameter, and stent type were found not to be predictive of DES ISR. In conclusion, correlates of DES ISR included both clinical and procedural factors. Limiting the number of stents and stented length, in addition to intravascular ultrasound guidance, may minimize DES ISR.