Drug-eluting stents (DESs) have been shown to reduce the rate of repeat revascularization compared with bare-metal stents (BMSs) after multivessel percutaneous coronary intervention in carefully selected patients. However, the long-term safety and efficacy of DESs in patients with multivessel disease outside the setting of randomized trials was unknown. Therefore, all patients undergoing multivessel percutaneous coronary intervention with BMSs, sirolimus-eluting stents (SESs), or paclitaxel-eluting stents (PESs) from January 2000 to December 2005 were investigated. The primary end point was all-cause mortality. A total of 1,720 patients were recruited in 3 consecutive sequential groups of BMS (n = 701; January 2000 to April 2002), SES (n = 293; April 2002 to February 2003), and PES (n = 726; February 2003 to December 2005). Overall median follow-up was 1,440 days. There was improved 3-year survival in the SES group (93.7%) compared with both the BMS (86.1%) and PES groups (87.3%), which remained significant after propensity score adjustment for differences in baseline and procedural characteristics (SES vs BMS, adjusted hazard ratio 0.53, 95% confidence interval 0.30 to 0.94; SES vs PES, adjusted hazard ratio 0.49, 95% confidence interval 0.28 to 0.87). There was no difference in mortality between the PES and BMS groups. Both DES types significantly reduced the need for clinically driven target-vessel and target-lesion revascularization without an excess in myocardial infarction or stent thrombosis. In conclusion, both SESs and PESs significantly reduced the need for repeated revascularization in these patients with no excess in mortality. SESs might reduce mortality in patients undergoing multivessel percutaneous coronary intervention.