Hypothyroidism and major depressive disorder (MDD) share neuropsychiatric features. Cerebral perfusion deficits are found in both disorders. We compared regional cerebral blood flow (rCBF) in hypothyroidism and MDD to determine if clinical similarities are mediated by common neurocircuitry. Ten hypothyroid and 10 depressed patients underwent 99mTc-HMPAO-SPECT and clinical evaluation before and after response to respective treatments. Ten healthy controls underwent a similar, single, evaluation. Before treatment, rCBF in hypothyroid and depressed patients was lower than in controls, in posterior and anterior aspects of the brain respectively. rCBF in hypothyroidism was lower than in MDD in right posterior cingulate and parieto/occipital regions, and higher in frontal, prefrontal and sub-genual regions. Reduced rCBF in pre- and post-central gyri was found in both groups. Following treatment, rCBF in depressed patients increased and normalized, but remained unchanged in hypothyroidism. Affective symptoms in hypothyroidism may be mediated by neurocircuitry different from that of major depression.