Single photon emission tomography (SPECT) with 99mTc-HMPAO was used to compare regional cerebral blood flow (rCBF) in patients with unipolar and bipolar depression. The study group consisted of 10 unipolar depressed patients and seven bipolar depressed patients who met the DSM-III-R criteria for major depressive disorder (MDD). Nine physically and mentally healthy volunteers served as control subjects. SPECT images were obtained in the patients at two time points: (1) during the major depressive episode before patients had received medication; and (2) at the beginning of the remitted state while patients were receiving antidepressant medication. During the depressive episode, unmedicated unipolar depressed patients showed relatively increased left frontal rCBF compared both with the control subjects and the bipolar patients (P < 0.05). No significant differences in rCBF emerged between the bipolar patients and the control subjects. The data suggest that unipolar depressed patients, unlike bipolar patients, have relatively increased rCBF in the left frontal lobes during the depressive episode, but these differences tend to disappear during the period of remission.