To determine whether changes in specific regions of the brain can contribute to the development of depression in patients with multiple sclerosis (MS). We prospectively studied 90 patients with clinically definite MS. Disability, independence, cognitive performances, and depressive and anxiety symptoms have been assessed at baseline and 2 years later. At these two time-points, patients underwent a 1.5-T magnetic resonance examination of the brain including T1- and T2-weighted images. Calculation of regional and total lesion loads (LL) have been performed by a semiautomatic technique; total and regional brain volumes have been calculated by a fully automatic highly reproducible computerized interactive program. Measurements of LL did not show any significant difference between depressed and non-depressed patients. Brain atrophy was significantly more conspicuous in the left frontal lobe (P=0.039), in both frontal lobes (P=0.046) and showed a trend towards a difference in the right frontal lobe (P=0.056), in the right temporal lobe (P=0.057) and in both temporal lobes (P=0.072) of depressed patients. Disability, independence and cognitive performances were similar in depressed and non-depressed patients (P=NS). Spearman correlation analysis and multiple-regression analysis demonstrated that the severity of the depressive symptoms score was associated both with the disability score and the right temporal brain volume. Destructive lesions in the right temporal lobe can contribute to the severity of depression in patients with MS but the influence of the severity of neurological impairment should be taken into account.