In 39 hospital inpatients with severe primary depressive disorders, we evaluated the relationships between subcortical hyperintensities on magnetic resonance imaging (MRI) and clinical features, neuropsychological impairment and response to standard therapies. Both white matter and gray nuclei lesions were associated with older age and the absence of a family history of affective disorder. White matter hyperintensities were also associated with onset of first affective episode after the age of 50 years and impaired psychomotor speed. Most importantly, the severity of white matter hyperintensities predicted a poorer response to treatment (r = -0.44, p < .01). Negative correlations of the same order were detected in those (n = 20) who received electroconvulsive therapy (r = -0.42, p = .06) and those (n = 19) who received pharmacotherapy alone (r = -.49, p < .05). This study provides preliminary evidence supporting the clinical and prognostic significance of extensive white matter hyperintensities in patients with severe depression.