In a selected group of right-handed patients with single stroke lesions of either the right (n = 14) or left (n = 22) hemisphere and no predisposing factors for psychiatric disorder, we found that the severity of depression was significantly increased in patients with left anterior lesions as opposed to any other lesion location. In addition, the severity of depression correlated significantly with proximity of the lesion on CT scan to the frontal pole in the left anterior group. The right hemisphere lesion group showed the reverse trend: patients with right posterior lesions were more depressed than patients with right anterior lesions, who were unduly cheerful and apathetic. These findings suggest that intrahemispheric lesion location is in some way related to mood disorder in stroke patients and that there is a graded effect of lesion location on severity of mood change. The neuroanatomy of the biogenic amine-containing pathways in the cerebral cortex might explain this graded effect and provide a neurochemical basis for the mood change.