Although drug-eluting stents (DESs) have been increasingly used in a wide variety of clinical and anatomic situations, limited data are available regarding the predictors of DES failure in unselected lesions. We investigated the incidence and predictors of restenosis after implantation of DESs in routine clinical practice. A total of 1,795 consecutive patients underwent successful implantation of sirolimus-eluting (1,374 patients, 1,788 lesions) or paclitaxel-eluting (421 patients, 517 lesions) stents. Of the 1,743 eligible patients (2,221 lesions), follow-up angiography at 6 months was obtained for 1,228 patients (70.5%, 1,577 lesions). All data were prospectively recorded and analyzed to predict the occurrence of restenosis, defined as a diameter stenosis of > or =50%. Restenosis was documented in 125 patients with 138 lesions (8.8%), and target lesion revascularization was required in 70 patients with 82 lesions (5.2%). The pattern of restenosis was 85 focal (62%), 29 diffuse (21%), 11 diffuse proliferative (8%), and 13 total (9%). Lesion length, stent length, postintervention minimal lumen diameter, preintervention minimal lumen diameter, reference artery size, complex lesions, and use of a paclitaxel-eluting stent were univariate predictors of restenosis. Multivariate analysis showed that the use of a paclitaxel-eluting stent (odds ratio [OR] 4.37, 95% confidence interval [CI] 2.90 to 6.58, p <0.001), postintervention minimal lumen diameter (OR 0.32, 95% CI 0.20 to 0.50, p <0.001), and lesion length (OR 1.02, 95% CI 1.01 to 1.04, p <0.001) were independent predictors of restenosis. In conclusion, the rate of restenosis after DES implantation in routine clinical practice was similar to the rate reported in clinical trials, confirming the efficacy of DES in routine clinical practice.