This study investigated the relationship between depression, physical disability, cognitive deficit and brain abnormalities on magnetic resonance imaging (MRI) in patients with early MS. Eighteen relapsing-remitting MS patients were evaluated: depression was diagnosed according to DSM-III R and measured by the MMPI depression subscale, physical disability was assessed by using the Kurtzke Expanded Disability Status Scale (EDSS) and cognitive functions by means of an extensive neuropsychological test battery. A neuroradiologist blinded to clinical findings quantified cerebral lesion on MRI. Weighted brain area lesion score were developed according to number and size of cerebral lesions. On the basis of DSM-III criteria, six patients were classified as having major depression, seven patients had minor depression and five patients were without depressive symptoms. No significant differences were found among the three groups on both neuropsychological performances and weighted MRI lesion scores. However patients with major depression exhibit greater physical disability than the other MS subgroups. A significant correlation was found between MMPI depression subscale and physical disability. This study suggests that at least in the early phase of MS, depression appears more related to the physical disability than to the severity of pathological brain involvement.