Background Currently, little data are available on the management of drug-eluting stent (DES) restenosis. Drug resistance may play a role in its etiology. Methods We identified all cases of either sirolimus-eluting or paclitaxel-eluting stent restenosis treated with repeated DES implantation. The lesions were divided into those receiving the same DES as the one that restenosed and those treated with the alternative DES. The end points analyzed were target lesion revascularization (TLR) and angiographic restenosis. Results We included 201 lesions (174 patients); the same DES was implanted in 107 lesions an a different DES in 94 lesions. Angiographic follow-up of the retreatment was available in 69.7% of the lesions. Angiographic restenosis occurred in 26.4% (19) of cases treated with the same DES and 25.8% (17) of those treated with a different DES (P = 1.0). Target lesion revascularization occurred in 15.9% (17) and 16% (15) of lesions, respectively (P = 1.0). A multivariate analysis confirmed the lack of association between the treatment selected and TLR (OR 0.7, 95% CIs [0.29-1.67]; P =.42). A nonfocal pattern of restenosis remained associated with TLR and restenosis (OR 2.99, 95% CIs [1.24-7.241; P = .015 and OR 3.6, 95% CIs [1.5-8.8]; P = .004, respectively). Conclusions Repeated DES implantation for DES restenosis is feasible and safe. The TLR rate is acceptable, with no differences between implantation of the same or a different DES. The pattern of restenosis treated is an important predictor of outcomes.