Depression is common in Alzheimer's disease (AD). Clinicoanatomic studies in focal brain injuries and functional imaging studies both in primary depression and in depression secondary to neurologic diseases have demonstrated involvement of the frontal lobe. Frontal involvement has not been established in the depression of AD. We studied the correlation between focal brain metabolic abnormalities and depression in AD. In 53 patients with probable AD of minimal to moderate disability, we assessed the severity of depression using the Neuropsychiatric Inventory and correlated the depression score with regional cerebral glucose metabolism determined by 18F-fluorodeoxyglucose and PET. Depression was present in 19 patients (36%). The depression score correlated significantly with normalized glucose metabolic rates in the bilateral superior frontal and left anterior cingulate cortices. These results indicated an association between depression and decreased activity in the frontal lobe in AD and support frontal involvement, especially in the left side, in depression, irrespective of disease etiology.