Background and Aim: Treatment of patients with left main coronary artery disease (LMCA) with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) remains controversial. The aim of this meta-analysis was to compare the long-term clinical outcomes of patients with unprotected LMCA treated randomly by PCI or CABG. Methods: PubMed, MEDLINE, Embase, Scopus, Google Scholar, CENTRAL and ClinicalTrials.gov database searches identified five randomized trials (RCTs) including 4499 patients with unprotected LMCA comparing PCI (n= 2249) vs. CABG (n= 2250), with a minimum clinical follow-up of five years. Random effect risk ratios were used for efficacy and safety outcomes. The study was registered in PROSPERO. The primary outcome was major adverse cardiac events (MACE), defined as a composite of death from any cause, myocardial infarction or stroke. Results: Compared to CABG, patients assigned to PCI had a similar rate of MACE (risk ratio (RR): 1.13; 95% CI: 0.94 to 1.36;p= 0.19), myocardial infarction (RR: 1.48; 95% CI: 0.97 to 2.25;p= 0.07) and stroke (RR: 0.87; 95% CI: 0.62 to 1.23;p= 0.42). Additionally, all-cause mortality (RR: 1.07; 95% CI: 0.89 to 1.28;p= 0.48) and cardiovascular (CV) mortality (RR: 1.13; 95% CI: 0.89 to 1.43;p= 0.31) were not different. However, the risk of any repeat revascularization (RR: 1.70; 95% CI: 1.34 to 2.15;p< 0.00001) was higher in patients assigned to PCI. Conclusions: The findings of this meta-analysis suggest that the long-term survival and MACE of patients who underwent PCI for unprotected LMCA stenosis were comparable to those receiving CABG, despite a higher rate of repeat revascularization.