OBJECTIVE Hyperintense lesions are a common finding on neuroimaging and are associated not only with aging, medical illness, and some invasive medical procedures, but also with neurologic and psychiatric morbidity. We hypothesized that hyperintense lesions are associated with alterations in white matter structure beyond the visible lesion boundaries as assessed with diffusion tensor imaging (DTI). METHODS Eighty-two neurologically intact older individuals completed brain MRI with DTI. DTI scans were analyzed using regions of interest placed in normal-appearing white matter to measure fractional anisotropy and diffusivity in the white matter of the frontal lobe, the genu of the corpus callosum, and the internal capsule. Hyperintense lesions volumes were measured separately in subcortical gray matter and anterior white matter through a semiautomated segmentation program. The relationship between lesion volumes and DTI measures was examined while controlling for patient age, patient sex, and total cerebral volume. RESULTS Greater anterior white matter lesion volumes were associated with higher diffusivity and lower anisotropy in the white matter of the dorsolateral prefrontal cortex and with higher diffusivity of the internal capsule and white matter lateral to the anterior cingulate cortex. Gray matter lesion volumes were associated with higher diffusivity in the genu of the corpus callosum and the internal capsule. CONCLUSIONS Ischemic hyperintense lesions are associated with widespread effects on the structure of the frontal lobe white matter and central white matter structures. This may reflect effects of lesions on neural circuits or identification of white matter changes that have not yet become visible on conventional MRI.