Cerebral white matter lesions (WML) seen on magnetic resonance imaging scans are associated with cardiovascular disease and vascular risk factors. To assess the association between WML and atherosclerosis, we studied 111 people, aged 65 to 85 years, randomly sampled, and stratified by age and sex, from participants in the Rotterdam Study. Cerebral T2-weighted magnetic resonance images in the axial plane were obtained for all subjects. Carotid atherosclerosis was ultrasonographically assessed by the presence of stenosis, measurement of intima to media wall thickness (IMT), and the presence of atherosclerotic plaques. A possible or definite myocardial infarction on an electrocardiogram was used as an indicator of coronary atherosclerosis. The ankle to arm systolic blood pressure ratio (ABI) was determined, and peripheral arterial disease was defined as an ABI lower than 0.90 in at least one side. Carotid atherosclerosis was significantly more pronounced in people with WML. The difference in common carotid IMT was 0.13 mm (95% confidence interval [CI] 0.04-0.21), whereas the odds ratio of WML associated with plaques in the carotid bifurcation was 3.9. The degree of internal carotid artery stenosis was not, however, associated with WML. The mean ABI was significantly lower in people with WML than in those without lesions with a difference of -0.11 (95% CI -0.21 to -0.01). The odds ratio of WML associated with peripheral arterial disease and a possible or definite myocardial infarction was 2.4 and 3.1, respectively. We conclude that atherosclerosis, indicated by increased common carotid IMT, carotid plaques, and a lower ABI, is related to WML.