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It is unclear whether brain MRI lesions are associated with depression in multiple sclerosis (MS). Neurological dysfunction in depressed (n = 19) and non-depressed (n = 29) MS patients was rated by expanded disability status scale (EDSS). EDSS was weakly predictive of the presence of (p = 0.03) and severity of (p = 0.01) depression. After correcting for EDSS, the presence of depression was predicted by superior frontal and superior parietal hypointense T1 lesions (p <0.01); the severity of depression was predicted by superior frontal, superior parietal and temporal T1 lesions, lateral and third ventricular enlargement, and frontal atrophy (p <0.01). Depression was not related to bright T2 lesions or enhancement. We conclude that atrophy and cortical–subcortical disconnection due to frontal and parietal white matter destructive lesions may contribute to depression in MS.