1. There is little published research on brain function in treatment-resistant depression (TRD). This study examined regional cerebral blood flow using 99mTechnetium-hexamethylpropanolamine oxime (HMPAO) single photon emission computed tomography in 8 patients with a history of TRD, 13 depressed patients without TRD (non-TRD) and 16 normal controls. 2. Relative HMPAO activity in selected brain regions revealed a significant increase in hippocampus-amygdala activity in TRD patients compared to non-TRD patients and healthy controls. The mean value of relative HMPAO activity did not differ in any other brain region, nor were there any differences in right-left symmetry among the subject groups. 3. The observation of increased hippocampus-amygdala HMPAO activity in TRD patients suggests that functional abnormalities in limbic circuitry may play a role in the pathophysiology of treatment-resistance.