Objective: Segmented brain white matter hyperintensities were compared between subjects with late-life depression and age-matched subjects with similar vascular risk factor scores. Correlations between neuropsychological performance and whole brain-segmented white matter hyperintensities and white and gray matter volumes were also examined. Method: Eighty-three subjects with latelife depression and 32 comparison subjects underwent physical examination, psychiatric evaluation, neuropsychological testing, vascular risk factor assessment, and brain magnetic resonance imaging (MRI). Automated segmentation methods were used to compare the total brain and regional white matter hyperintensity burden between depressed patients and comparison subjects. Results: Depressed patients and comparison subjects did not differ in demographic variables, including vascular risk factor, or whole brain-segmented volumes. However, depressed subjects had seven regions of greater white matter hyperintensities located in the following white matter tracts: the superior longitudinal fasciculus, fronto-occipital fasciculus, uncinate fasciculus, extreme capsule, and inferior longitudinal fasciculus. These white matter tracts underlie brain regions associated with cognitive and emotional function. In depressed patients but not comparison subjects, volumes of three of these regions correlated with executive function; whole brain white matter hyperintensities correlated with executive function; whole brain white matter correlated with episodic memory, processing speed, and executive function; and whole brain gray matter correlated with processing speed. Conclusions: These findings support the hypothesis that the strategic location of white matter hyperintensities may be critical in late-life depression. Further, the correlation of neuropsychological deficits with the volumes of whole brain white matter hyperintensities and gray and white matter in depressed subjects but not comparison subjects supports the hypothesis of an interaction between these structural brain components and depressed status.