Mitral annular calcium (MAC) has been shown to be an independent predictor of stroke, but the basis for this association remains incompletely defined. This study was conducted to investigate the extent to which aortogenic embolism may mediate the MAC-stroke relation. In a cross-sectional study of patients referred for transesophageal echocardiography for the evaluation of cerebral ischemia, the relation between MAC and proximal and distal complex aortic atheroma (CAA) was assessed. In 419 patients composing the study cohort, MAC was associated with atherosclerosis risk factors, previous cardiovascular disease, atrial fibrillation, ipsilateral large-artery stenosis, left-sided cardiac abnormalities, and aortic valve calcium. MAC was associated with CAA of the proximal and distal thoracic aorta in unadjusted analyses, and these associations became stronger with increasing MAC severity. After adjustment for clinical and echocardiographic covariates, MAC exhibited a significant association with proximal and distal CAA in the entire cohort. In patients without alternative potential mechanisms for cerebral ischemia, however, the relation with proximal CAA became more pronounced (adjusted odds ratio 2.74, 95% confidence interval 1.22 to 6.16), but that for distal CAA changed little and became nonsignificant (adjusted odds ratio 1.97, 95% confidence interval 0.87 to 4.45). In conclusion, MAC was significantly associated with proximal and distal CAA independent of clinical and echocardiographic covariates in this cohort with cerebral ischemia, but in subjects without identifiable alternative mechanisms, the magnitude of the relation increased only for proximal CAA. These findings support the role of proximal CAA as a direct mediator of the increased stroke risk associated with MAC.