Background: Dual antiplatelet therapy (DAPT) with a potent P2Y ₁₂ Inhibitor coupled with aspirin for 1 year is the recommended treatment for patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Alternatively, monotherapy with a P2Y ₁₂ inhibitor after a short period of DAPT has emerged as a bleeding reduction strategy. Methods: We pooled individual patient data from randomized trials that included ACS patients undergoing PCI treated with an initial 3-month course of DAPT followed by ticagrelor monotherapy versus continued ticagrelor plus aspirin. Patients sustaining a major ischemic or bleeding event in the first 3 months after PCI were excluded from analysis. The primary outcome was Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding occurring between 3 and 12 months after index PCI. The key secondary endpoint was the composite of death, myocardial infarction (MI), or stroke. Hazard ratios (HR) and 95% confidence intervals (CI) were generated using Cox regression with a one-stage approach in the intention to treat population. Results: The pooled cohort (N = 7,529) was characterized by a mean age of 62.8 years, 23.2% of patients were female and 55% presented with biomarker positive ACS. Between 3 and 12 months, ticagrelor monotherapy significantly reduced BARC 3 or 5 bleeding as compared with ticagrelor plus aspirin (0.8% vs. 2.1%; HR 0.37, 95% CI 0.24-0.56; p < 0.001). Rates of all-cause death, MI, or stroke were not significantly different between groups (2.4% vs. 2.7%; HR 0.91, 95% CI 0.68-1.21; P = 0.515). Findings were unchanged among patients presenting with biomarker positive ACS. Conclusions: Among ACS patients undergoing PCI who have completed a 3-month course of DAPT, discontinuation of aspirin followed by ticagrelor monotherapy significantly reduced major bleeding without incremental ischemic risk, as compared with ticagrelor plus aspirin.