Background: Uncertainty remains about the effects of aspirin in patients with prior percutaneous coronary intervention (PCI) having noncardiac surgery. Objective: To evaluate benefits and harms of perioperative aspirin in patients with prior PCI. Design: Nonprespecified subgroup analysis of a multicenter factorial trial. Computerized Internet randomization was done between 2010 and 2013. Patients, clinicians, data collectors, and outcome adjudicators were blinded to treatment assignment. (ClinicalTrials.gov: NCT01082874) Setting: 135 centers in 23 countries. Patients: Adults aged 45 years or older who had or were at risk for atherosclerotic disease and were having noncardiac surgery. Exclusions were placement of a bare-metal stent within 6 weeks, placement of a drug-eluting stent within 1 year, or receipt of nonstudy aspirin within 72 hours before surgery. Intervention: Aspirin therapy (overall trial, n = 4998; subgroup, n = 234) or placebo (overall trial, n = 5012; subgroup, n = 236) initiated within 4 hours before surgery and continued throughout the perioperative period. Of the 470 subgroup patients, 99.9% completed follow-up. Measurements: The 30-day primary outcome was death or nonfatal myocardial infarction; bleeding was a secondary outcome. Results: In patients with prior PCI, aspirin reduced the risk for the primary outcome (absolute risk reduction, 5.5% [95% CI, 0.4% to 10.5%]; hazard ratio [HR] , 0.50 [CI, 0.26 to 0.95]; P for interaction = 0.036) and for myocardial infarction (absolute risk reduction, 5.9% [CI, 1.0% to 10.8%] ; HR, 0.44 [CI, 0.22 to 0.87]; P for interaction = 0.021). The effect on the composite of major and life-Threatening bleeding in patients with prior PCI was uncertain (absolute risk increase, 1.3% [CI, -2.6% to 5.2%] ). In the overall population, aspirin increased the risk for major bleeding (absolute risk increase, 0.8% [CI, 0.1% to 1.6%]; HR, 1.22 [CI, 1.01 to 1.48] ; P for interaction = 0.50). Limitation: Nonprespecified subgroup analysis with small sample. Conclusion: Perioperative aspirin may be more likely to benefit rather than harm patients with prior PCI. Primary Funding Source: Canadian Institutes of Health Research. © 2018 American College of Physicians.