Depression is a common mood disturbance in multiple sclerosis (MS) patients. Epidemiologic data suggest a causative relationship between depressive symptoms and cerebral demyelination, although a specific lesion site responsible for depressed mood has not been identified. Given that depression in neurologic disease is closely related to frontal and temporal lobe damage, we focused our study on investigating the extent to which lesions in the white matter connecting both cerebral lobes may account for depressive symptoms in MS. Forty-five patients were assessed using the Beck Depression Inventory and an MRI protocol conceived to quantify lesions separately in the basal, medial, and lateral frontotemporal white matter. The presence of lesions in the left suprainsular white matter, the region that mainly includes the arcuate fasciculus, was specifically associated with depressive symptoms, accounting for a significant 17% of the depression score variance. Although a multifactorial origin is suspected for depression in MS, this finding gives support to the existence of a direct negative effect of demyelination on mood.