The purpose of this study was to review our experience with left main stenting and evaluate initial results with drug-eluting stents (DESs). Drug-eluting stents delivered with contemporary techniques could change the traditional surgical approach to patients with significant left main disease. One hundred sixty-one patients underwent left main stenting (100 bare metal, 61 drug-eluting) after being excluded from surgery. In group A, disease was confined to the ostium or main stem; in group B, disease involved the bifurcation. Patients were classified as either unprotected (U) or protected (P) depending on the presence of a patent bypass graft. Study endpoints were any major adverse cardiac event (MACE). In-hospital MACE was 6% with no deaths; 74% of patients in group A underwent direct stenting, whereas 89% of the patients in group B had predilatation performed prior to stent implantation. A total of 98% of patients in BU had kissing balloon inflations after stent deployment; provisional side-branch stenting was required in one patient. V-stenting was performed in 13% of patients in group BU. The 1-year mortality in the bare metal stent group was 9% with the majority of deaths in group BU. There was one noncardiac death in the DES group at 6 months and five patients (8.2%) underwent target vessel revascularization for restenosis. Event-free survival at 6 months in group BU treated with DESs was 87%. Significant left main disease presents a spectrum of angiographic abnormalities and different interventional techniques are required depending on lesion location and distal protection. Although in-hospital complications with left main stenting were low in this single-center study, follow-up events were common in patients treated with bare metal stents. A randomized multicenter trial will be required to determine whether drug-eluting stents will improve survival in patients with left main disease.