Percutaneous treatment of unprotected left main coronary artery (ULMCA) stenosis using drug-eluting stents (DES) has been suggested as the best approach for patients who are poor surgical candidates. Some concerns have recently been raised regarding the risk of stent thrombosis following DES implantation. This study was performed in order to evaluate the safety of DES, as compared to bare metal stents (BMS), for ULMCA stenosis treatment in very high risk patients with a high likelihood of stent thrombosis. Forty-two consecutive patients were treated with either BMS (20) or DES (22) for ULMCA critical stenosis. Inclusion criteria were: ST elevation myocardial infarction, non-ST elevation myocardial infarction, cardiogenic shock, or logistic European System for Cardiac Operative Risk Evaluation ≥13%. At 1 year, one case of late thrombosis and three cases of restenosis were reported in the BMS group and none in the DES group, leading to a significantly inferior rate of target lesion revascularization (20.0 vs. 0%, p = 0.048) and major adverse cardiac events (65.0 vs. 19%, p = 0.004). DES placement for ULMCA stenosis also appears to be a safe therapeutic choice in very high-risk patients, as it provides the benefit of a reduction in restenosis without increasing the risk of early or late stent thrombosis.