To compare the efficacy and safety of dual antiplatelet therapy (DAPT) and triple therapy (TT, dual antiplatelet plus warfarin) in patients with myocardial infarction (MI) or PCI with stenting (PCI-S) who also require chronic oral anticoagulation. Background: Recommendations for the optimal antiplatelet/anticoagulant treatment regimen for patients undergoing PCI-S or MI who also require oral anticoagulation are largely based on evidence from observational studies and expert opinions. Methods: A systematic search was performed for studies comparing TT vs. DAPT in patients post PCI-S or MI and requiring chronic anticoagulation. Primary outcome was all-cause mortality. Secondary outcomes were ischemic stroke, major bleeding, MI, and stent thrombosis. Pooled relative risks (RR) were calculated using random effects model. Results: A total of 17 studies were included, with 14,921 patients [TT: 5,819(39%) and DAPT: 9,102(61%)] and a mean follow-up of 1.6 years. The majority of patients required oral anticoagulation for atrial fibrillation. Compared to DAPT, patients treated with TT had no significant difference in all-cause mortality [RR: 0.81, 95% confidence interval (CI): 0.61–1.08,P = 0.15], MI [RR 0.74, 95% CI: 0.51–1.06,P = 0.10], and stent thrombosis [RR 0.67, 95% CI: 0.35–1.30,P = 0.24]. Patients treated with TT had significantly increased risk of major bleeding [RR 1.20, 95% CI: 1.03–1.39,P = 0.02], whereas the risk for ischemic stroke was significantly lower [RR 0.59, 95% CI: 0.38-0.92,P = 0.02]. Conclusions: All-cause mortality appears similar in patients treated with TT or DAPT although TT was associated with higher rates of major bleeding and a lower risk for ischemic stroke.