Background and Purpose: Covert brain infarcts are associated with cognitive decline. It is not known whether therapies that prevent symptomatic stroke prevent covert infarcts. COMPASS compared rivaroxaban with and without aspirin with aspirin for the prevention of stroke, myocardial infarction, and vascular death in participants with stable vascular disease and was terminated early because of benefits of rivaroxaban 2.5 mg twice daily plus aspirin over aspirin. We obtained serial magnetic resonance imagings and cognitive tests in a consenting subgroup of COMPASS patients to examine treatment effects on infarcts, cerebral microbleeds, and white matter hyperintensities. Methods: Baseline and follow-up magnetic resonance imagings were completed in 1445 participants with a mean (SD) interval of 2.0 (0.7) years. Whole-brain T1, T2 fluid-attenuated inversion recovery, T2* sequences were centrally interpreted by blinded, trained readers. Participants had serial measurements of cognition and function. The primary end point was the proportion of participants with incident covert infarcts. Secondary end points were the composite of clinical stroke and covert brain infarcts, cerebral microbleeds, and white matter hyperintensities. Results: At baseline, 493 (34.1%) participants had infarcts. Incident covert infarcts occurred in 55 (3.8%) participants. In the overall trial rivaroxaban plus aspirin reduced ischemic stroke by 49% (0.7% versus 1.4%; hazard ratio [95% CI], 0.51 [0.38–0.68]). In the magnetic resonance imaging substudy the effects of rivaroxaban+aspirin versus aspirin were: covert infarcts: 2.7% versus 3.5% (odds ratio [95% CI], 0.77 [0.37–1.60]); Covert infarcts or ischemic stroke: 2.9% versus 5.3% (odds ratio [95% CI], 0.53 [0.27–1.03]). Incident microbleeds occurred in 6.6% of participants and 65.7% of participants had an increase in white matter hyperintensities volume with no effect of treatment for either end point. There was no effect on cognitive tests. Conclusions: Covert infarcts were not significantly reduced by treatment with rivaroxaban and aspirin but estimates for the combination of ischemic stroke and covert infarcts were consistent with the effect on ischemic stroke in the overall trial. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01776424.