BACKGROUND: The probable complications of 3 different cardiovascular diseases treatment options including percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), and medical therapy (MT), especially in individuals suffering from left main (LM) and/or three vessel diseases (3VDs), have received less attention. Thus, the aim of this study was to compare the complications of the aforementioned therapeutic strategies in patients admitted with LM coronary artery disease (CAD) and/or having 3VDs.METHODS: From March 2018 to March 2019, a total number of 251 eligible individuals (87, 86, and 78 subjects treated with PCI, CABG, and MT, respectively) were recruited in this cohort study. After the initiation of treatment, all individuals were followed for 6 months. Occurrence of any complications including chest pain (CP), re-hospitalization due to cardiac problems, heart failure (HF), death, myocardial infarction (MI), and stroke as well as major adverse cardiac events (MACE) were assessed.RESULTS: Significantly lower percentages of CP, readmission, and HF were observed in the CABG group compared to the PCI and MT groups (24.4% vs. 47.1% and 53.9%, P < 0.001; 3.5% vs. 13.8% and 5.1%, P = 0.020; 1.2% vs. 2.3% and 9%; P = 0.040, respectively). Further analysis revealed an increased likelihood of hospitalization in the PCI group (OR: 3.82, 95% CI: 1.01-14.41, P = 0.040), and a lower risk of CP and HF occurrence in the CABG group subjects compared to the MT group (OR: 0.28, 95% CI: 0.13-0.62, P = 0.002 and OR: 0.05, 95% CI: 0.004-0.71, P = 0.030, respectively). This pattern was also observed in the PCI group in terms of HF (OR: 0.12, 95% CI: 0.02-0.83, P = 0.030).CONCLUSION: Patients suffering from LM and/or 3VDs would most likely benefit from CABG followed by PCI, rather than MT. Further large-scale studies are required to confirm these results.