Although octogenarians are increasingly referred for percutaneous coronary intervention (PCI), data are lacking on long-term safety and efficacy of drug-eluting stents in this high-risk subpopulation. The aim of this study was to evaluate 5-year clinical outcome of octogenarians who underwent PCI using sirolimus-eluting stents (SESs) or paclitaxel-eluting stents (PESs) compared to bare-metal stents (BMSs). From January 2000 to December 2005, 319 consecutive octogenarian patients who underwent PCI with BMSs (n = 93, January 2000 to April 2002), SESs (n = 52, April 2002 to February 2003), or PESs (n = 174, February 2003 to December 2005) were included prospectively. Primary study end points were all-cause mortality and major adverse cardiac events (MACEs), defined as all-cause death, any myocardial infarction, or any revascularization. Mean age of the study population was 83 ± 2 years and 51% of patients were men. Median follow-up duration was 5.4 years (range 3 to 9). Five-year mortality rates in the BMS, SES, and PES cohorts were similar (41%, 42%, and 41%, respectively). Cumulative 5-year MACE-free survival in the BMS, SES, and PES cohorts were 44%, 52%, and 48%, respectively. Compared to the BMS cohort, adjusted hazard ratios for MACEs in the SES and PES cohorts were 0.5 (95% confidence interval [CI] 0.3 to 0.9, p <0.05) and 0.5 (95% CI 0.2 to 1.4, p = 0.2), respectively. Overall, use of drug-eluting stents was associated with fewer MACEs (adjusted hazard ratio 0.5, 95% CI 0.3 to 0.9, p <0.05) and a trend toward less target vessel revascularization (adjusted hazard ratio 0.5, 95% CI 0.2 to 1.2, p = 0.1). In conclusion, PCI with drug-eluting stents in octogenarians was found to be safe and more effective compared to PCI with BMSs.