A third of ischemic strokes and transient ischemic attacks have no known cause. Several studies have reported that complex atherosclerotic debris in the aorta is an independent risk factor for these events. A case–control study conducted by researchers at the Mayo Clinic, however, has now cast doubt on these conclusions. From 1993 to 1997, the study assessed 1,135 individuals who underwent transesophageal echocardiography. The study population included 520 randomly selected controls, 329 controls referred for transesophageal echocardiography, 159 cases of noncryptogenic ischemic events and 127 cases of cryptogenic ischemic events. When adjusted for ischemic stroke risk factors, no association was found between complex atherosclerotic debris in the aortic arch and cryptogenic stroke, although an association between such debris and non cryptogenic stroke was suggested (odds ratio 3.16, 95% CI 1.18–8.51). The authors suggest that methodological differences might explain the different outcome of this study compared with previous work. In particular, they point to steps taken to minimize selection and referral bias and to the inclusion of an adjustment variable to control for generalized atherosclerosis. The results of the study suggest that complex aortic debris is a marker for other ischemic risk factors rather than a cause of cryptogenic stroke.