Signal hyperintensities on magnetic resonance imaging (MRI) are increased in the white matter (WMH) and deep gray matter in dementia and depression and may have similar pathologies. However, no previous study has examined WMH in subjects with major depression. We carried out in vitro MRI on brain tissue from elderly subjects who had suffered major depression and elderly control subjects to identify and rate WMH. The tissue was subsequently prepared for histopathological analysis using a number of conventional and immunohistochemical stains, and the WMH were examined to identify their underlying pathological causes. Cerebral microvessels were also assessed and the findings compared with assessments of atheromatous disease in these subjects. PVH were found to be due to one of three causes: dilated perivascular spaces (with and without ischemia in the perivascular area), oligemic demyelination, and ischemic demyelination. DWMH also showed three types of causes: dilated perivascular spaces (with and without ischemia in the perivascular area), oligemic demyelination, and ischemic demyelination. Cerebral microvascular disease only contributed to a few of the lesions and atheromatous disease did not show associations with WMH in these subjects. These findings are similar to previous reports in other diseases and demonstrate WMH in elderly depression to be a manifestation of cerebrovascular disease. However, since large vessel and small vessel disease were not associated with WMH, our findings suggest hypotensive disease might be an important and unrecognized mechanism underlying WMH in late-life depression.