BACKGROUND AND PURPOSE: Apolipoprotein E (apoE) alleles (epsilon2 and epsilon4) are associated with cerebral amyloid angiopathy, in which white matter disease and microbleeds are prominent features. The role of apoE in patients with microbleeds or white matter disease but no evidence of cerebral amyloid angiopathy has not been elucidated. We studied apoE alleles in relation to white matter disease and microbleeds in patients with transient ischemic attack or ischemic stroke. METHODS: We obtained brain MRI scans and apoE genotypes in 334 transient ischemic attack or ischemic stroke patients. Microbleeds were scored on a gradient echo MRI and white matter disease was examined on fluid attenuated inversion recovery MRI using a semiquantitative rating scale. RESULTS: Patients with moderate to severe white matter disease more frequently carried apoE epsilon2 alleles (25.2% versus 11.3%, P=0.001), but not apoE epsilon4 (26.6% in apoE epsilon4 carriers versus 25.9%; P=0.98). Adjustment for traditional risk factors did not modify this relationship (odds ratio, 2.9; 95% confidence interval, 1.5 to 5.3). There was no association between the presence of microbleeds and the apoE epsilon4 or apoE epsilon2 alleles. CONCLUSIONS: ApoE alleles do not exert a major influence on the development of microbleeds, but apoE epsilon2 may be associated with development of moderate to severe white matter disease in transient ischemic attack and stroke patients.