The authors examined the individual and relative roles of atrophy, comorbid medical illness, and cerebrovascular risk factors in the pathogenesis of late-life major depressive disorder (MDD). They used magnetic resonance imaging techniques to study 28 subjects with late-life MDD, 29 healthy control subjects, and 34 subjects with probable dementia of the Alzheimer type (DAT). Depressed subjects showed increases in cerebrospinal fluid volumes comparable to the DAT group but significantly different from control subjects. High-intensity signals, but not measures of atrophy correlated significantly with cerebrovascular risk factor scores. A logistic regression revealed that both brain atrophy and medical illness are associated with an increased risk of developing MDD. Data suggest that both atrophy and comorbid medical illness increase the likelihood of developing MDD in late life.