Objective ·To compare the perioperative and short-to-medium-term clinical outcomes of minimally invasive multivessel cardiac surgery-coronary artery bypass grafting (MICS-CABG) and hybrid coronary revascularization (HCR) in patients with multivessel coronary artery disease (CAD), and to evaluate their safety and clinical applicability. Methods ·A retrospective analysis was conducted on 123 patients who underwent minimally invasive coronary artery bypass surgery at the Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, between January 2020 and June 2023. Patients were divided into the MICS-CABG group (n=58) and the HCR group (n=65) based on the surgical approach. Baseline characteristics [smoking history, hypertension, diabetes, chronic obstructive pulmonary disease (COPD), history of cerebral infarction, myocardial infarction, prior percutaneous coronary intervention (PCI), left ventricular ejection fraction (LVEF), number of diseased coronary vessels] and perioperative outcomes [operation time, perioperative transfusion, conversion to median sternotomy, intra-aortic balloon pump (IABP) or extracorporeal membrane oxygenation (ECMO) use, reoperation for any cause, mechanical ventilation duration, intensive care unit (ICU) stay, hospital stay, number of revascularized vessels, 24-hour postoperative drainage volume, mortality, and complications] were compared. Follow-up was conducted at 1, 3, 6, and 12 months postoperatively and every 6 months thereafter, with the primary endpoint being major adverse cardiac and cerebrovascular events (MACCE). Coronary imaging was performed at (12±3) months to assess graft/stent patency. Results ·The MICS-CABG group had a significantly longer operative time (P<0.001), a longer duration of mechanical ventilation (P=0.001), and a higher incidence of early postoperative respiratory failure (32.76% vs 12.31%, P=0.007) compared to the HCR group. However, the MICS-CABG group achieved more complete revascularization (P=0.002). Postoperative 24-hour drainage volume was greater in the MICS-CABG group (P<0.001), but transfusion rates did not differ significantly (6.90% vs 1.54%, P=0.145). Conversion to sternotomy, IABP implantation, and ECMO use were not required in either group. No significant differences were observed in perioperative myocardial infarction, stroke, new-onset atrial fibrillation, mortality, ICU stay, or hospital stay. In the MICS-CABG group, 170 grafts were anastomosed [58 left anterior descending (LAD) grafts and 112 non-LAD grafts], while the HCR group had 65 grafts (all LAD) and 90 PCI-treated vessels. At 1 year, LAD graft patency (93.10% vs 96.92%, P=0.601) and non-LAD target vessel patency (91.96% vs 96.67%, P=0.190) showed no significant differences. The MICS-CABG group patients were followed up for (30±22) months postoperatively, and the HCR group patients were followed up for (31±16) months postoperatively. MACCE rates were low in both groups (MICS-CABG 0 vs HCR 1.54%, P=0.325), with no significant difference in repeat revascularization. Conclusion ·MICS-CABG and HCR demonstrate comparable perioperative safety and short-to-medium-term efficacy in patients with multivessel CAD. While MICS-CABG requires a longer operative time and carries a higher risk of respiratory complications, HCR necessitates stringent PCI eligibility assessment. The choice of procedure should be individualized based on anatomical complexity and cardiopulmonary function.