Background Although target lesion revascularization (TLR) has been dramatically decreased by using drug-eluting stents (DESs) in de-novo lesions, their efficacy for in-stent restenosis (ISR) has not yet been well established. Methods We retrospectively analysed patients treated for ISR with DESs from three referral hospitals. Results Eighty-seven consecutive patients, from June 2002 to April 2004, were included, with a mean age of 64 +/- 11 years; 83% were men, 32% had diabetes, 47% had had a previous myocardial infarction and 16% had low left ventricular ejection fraction. Angiographic characteristics were as follows: mean vessel diameter, 3.05 +/- 0.4 mm; lesion length, 17.8 +/- 7.7 mm; diameter stenosis, 84.0 +/- 10.7%; and complex lesion, 81%. The restenosis was focal in 45%, diffuse/proliferative in 51.3% and total occlusion in 3.7% of the cases. Sirolimus- and paclitaxel-eluting stents were used in 42 and 58% of the patients, respectively. Stent diameter was 3.1 +/- 0.3 mm and the length was 26.1 +/- 5.8 mm. Angiographic success was achieved in all patients, with one patient experiencing a post-procedural non-Q-wave myocardial infarction. At 6-month clinical follow-up, two patients had died from non-cardiac deaths, five had experienced a new TLR (5.7%, four percutaneous and one coronary artery bypass graft) and eight (9.2%) had had major adverse cardiac events. A stress test was performed in 60% of the population; target vessel ischemia was observed in one patient (3.3%). Conclusion In this non-select cohort of patients, the use of DESs is a safe and effective strategy for ISR lesions.