This study was conducted to further establish the significance of the previously reported association between depressive symptoms and demyelinating lesions in the region of the left arcuate fasciculus in multiple sclerosis patients. The Beck Depression Inventory (BDI) was broken down into its main symptom categories on the basis of well-established factor analyses from the literature, and the correlation pattern between the resulting BDI subscores and lesion measurements was analyzed. We found that lesions of the left arcuate fasciculus region were selectively associated with BDI items expressing patients' Affective Symptoms and Somatic Complaints. Specifically, lesion measurements from this brain location accounted for 26% of symptom score variance of the BDI part that includes only these two factors. Performance Difficulties and Cognitive Distortions were not consistently associated with the lesion measurement. Performance Difficulties, however, showed a high correlation with the neurologic deficit detected in the physical examination. These results show that lesions in the left arcuate fasciculus region are associated with the core of the depressive syndrome rather than marginal symptoms and, thus, further suggest that this left suprainsular brain region involves white matter tracts relevant to mood regulation.