Background It is still controversial whether percutaneous coronary intervention with drug-eluting stent (DES) is safe and effective compared to coronary artery bypass graft surgery (CABG) for unprotected left main coronary artery (ULMCA) disease at long-term follow up (≥ 3 years). Methods Eligible studies were selected by searching PubMed, EMBASE, and Cochrane Library up to December 6, 2016. The primary endpoint was a composite of death, myocardial infarction (MI) or stroke during the longest follow-up. Death, cardiac death, MI, stroke and repeat revascularization were the secondary outcomes. Results Four randomized controlled trials and twelve adjusted observational studies involving 14,130 patients were included. DES was comparable to CABG regarding the occurrence of the primary endpoint (HR = 0.94, 95% CI: 0.86-1.03). Besides, DES was significantly associated with higher incidence of MI (HR = 1.56, 95% CI: 1.09-2.22) and repeat revascularization (HR = 3.09, 95% CI: 2.33-4.10) compared with CABG, while no difference was found between the two strategies regard as the rate of death, cardiac death and stroke. Furthermore, DES can reduce the risk of the composite endpoint of death, MI or stroke (HR = 0.80, 95% CI: 0.67-0.95) for ULMCA lesions with SYNTAX score ≤ 32. Conclusions Although with higher risk of repeat revascularization, PCI with DES appears to be as safe as CABG for ULMCA disease at long-term follow up. In addition, treatment with DES could be an alternative interventional strategy to CABG for ULMCA lesions with low to intermediate anatomic complexity.