BACKGROUND: It remains unclear whether indobufen-based dual antiplatelet therapy (DAPT) preserves ischemic protection while limiting bleeding risk in patients with multivessel coronary disease (MVD). This study aimed to investigate the efficacy and safety of indobufen-based DAPT in patients with MVD. METHODS: Patients in the OPTION trial were stratified based on the presence of MVD. We compared the ischemic and bleeding risks of indobufen-based DAPT (indobufen 100mg twice a day plus clopidogrel 75 mg/d for 12 months) vs conventional DAPT (aspirin 100 mg/d plus clopidogrel 75 mg/d for 12 months) in patients with and without MVD, using landmarks at 6 months and 1-year post-percutaneous coronary intervention (PCI). RESULTS: Patients with MVD tended to be older and contained a higher prevalence of high-risk features. Compared with patients without MVD, those with MVD were at higher risk for net adverse clinical events and ischemic events. The risk of ischemic events between indobufen-based DAPT vs conventional DAPT was similar either in patients with MVD or without MVD during the first and second 6 months. During the first 6 months, indobufen-based DAPT decreased the risk of bleeding events consistently in patients with and without MVD. Of note, during the second 6 months, indobufen-based DAPT continually decreased the risk of bleeding events in patients with MVD but not in those without MVD. CONCLUSIONS: In patients with MVD, indobufen plus clopidogrel DAPT compared to aspirin plus clopidogrel DAPT could reduce the risk of bleeding events while preserving ischemic protection during both the first and second 6 months post-PCI. Indobufen presents an effective option for patients with MVD, especially those at high ischemic risk requiring DAPT beyond 6 months post-PCI. TRIAL REGISTRATION: The trial was registered at www.chictr.org. A Randomized Controlled Trial of Indobufen vs Aspirin after Coronary Drug-eluting Stent Implantation: the OPTION Trial (ChiCTR-IIR-17013505).