Severe aortic plaques seen on transesophageal echocardiography (TEE) are a high-risk cause of stroke and peripheral embolization. Evidence to guide therapy is lacking. Retrospective information was obtained regarding the occurrence of embolic events (stroke, transient ischemic attacks, or peripheral emboli) in 519 patients with severe thoracic aortic plaque seen on TEE since 1988. Treatment with statins, warfarin, or antiplatelet medications was noted. Treatment was not randomized. In a matched-paired analysis, each patient taking each class of therapy was matched for age, gender, previous embolic event, hypertension, diabetes, congestive failure, and atrial fibrillation to someone not taking that medication. Multivariate analysis was also performed. An embolic event occurred in 111 patients (21%). Multivariate analysis showed that statin use was independently protective against recurrent events (p = 0.0001). Matched analysis also showed a protective effect of statins (p = 0.0004; absolute risk reduction 17%, relative risk reduction 59%, number needed to treat [n = 6]). No protective effect was found for warfarin or antiplatelet drugs. The odds ratio for embolic events was 0.3 (95% confidence interval [CI] 0.2 to 0.6) for statin therapy, 0.7 (95% CI 0.4 to 1.2) for warfarin, and 1.4 (95% CI 0.8 to 2.4) for antiplatelet agents. Thus, there is a protective effect of statin therapy, and no significant benefit of warfarin or antiplatelet drugs on the incidence of stroke and other embolic events in patients with severe thoracic aortic plaque on TEE.