Background - The angiographic presentation of in-stent restenosis (ISR) may convey prognostic information on subsequent target vessel revascularizations (TLR). Methods and Results - We developed an angiographic classification of ISR according to the geographic distribution of intimal hyperplasia in reference to the implanted stent. Pattern I includes focal (≤ 10 mm in length) lesions, pattern II is ISR> 10 mm within the stent, pattern III includes ISR> 10 mm extending outside the stent, and pattern IV is totally occluded ISR. We classified a total of 288 ISR lesions in 245 patients and verified the angiographic accuracy of the classification by intravascular ultrasound. Pattern I was found in 42% of patients, pattern II in 21%, pattern III in 30%, and pattern IV in 7%. Previously recurrent ISR was more frequent with increasing grades of classification (9%, 20%, 34%, and 50% for classes I to IV, respectively; P=0.0001), as was diabetes (28%, 32%, 39%, and 48% in classes I to IV, respectively; P<0.01). Angioplasty and stenting were used predominantly in classes I and II, whereas classes III and IV were treated with atheroablation. Final diameter stenosis ranged between 21% and 28% (P=NS among ISR patterns). TLR increased with increasing ISR class; it was 19%, 35%, 50%, and 83% in classes I to IV, respectively (P<0.001). Multivariate analysis showed that diabetes (odds ratio, 2.8), previously recurrent ISR (odds ratio, 2.7), and ISR class (odds ratio, 1.7) were independent predictors of TLR. Conclusions - The introduced angiographic classification is prognostically important, and it may be used for appropriate and early patient triage for clinical and investigational purposes.