Background Late vessel failure by restenosis or thrombosis is a potential limitation of drug-eluting stent implantation. Methods We conducted a prospective 5-year clinical evaluation following implantation of sirolimus-eluting Cypher stents for in-stent restenosis regardless of the patient's symptomatic status. A complete 5-year follow-up is reported for 192 consecutive patients. Results The cumulative rate of death was 5.2%, of cardiac death was 4.2%, of nonfatal myocardial infarction was 4.2%, of definite stent thrombosis was 1.0%, of probable stent thrombosis was 1.0%, of possible stent thrombosis was 2.1%, of target lesion revascularization was 9.4%, of target vessel revascularization was 13.5%, and of major adverse cardiovascular events (death of all causes, nonfatal myocardial infarction, and repeat revascularization; major adverse cardiovascular event) was 22.9%, respectively. Conclusion These results, of a comparably large series, indicate that the implantation of sirolimus-eluting Cypher stents for the treatment of coronary in-stent restenosis is effective and safe and associated with a stable clinical course in the very long term. Coron Artery Dis 22:188-193 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.