Compromised regional cerebral blood flow (rCBF) in major depressive disorder may be partly reversed by successful antidepressant treatment. However, it is not known if the reversal of rCBF compromise is dependent on the mode of antidepressant treatment. The current study aimed to address this question. Thirty-three patients (19 women and 14 men; mean age +/- SD, 53 +/- 16 y) with moderate major depressive disorder were studied before 6 wk of treatment with tricyclic antidepressants, selective serotonin reuptake inhibitors, or a course of electroconvulsive therapy, and 31 of these patients were also studied afterward. A comparison group of 25 healthy volunteers (13 women and 12 men; mean age, 49 +/- 15 y) were studied once. rCBF was assessed using 99mTc-hexamethylpropyleneamine oxime SPECT. Images were analyzed using globally normalized statistical parametric mapping localized to the Montreal Neurologic Institute brain atlas. Baseline rCBF was lower in depressed patients than in controls in the frontal cortex and subcortical nuclei bilaterally. A response to medication was associated with normalization of rCBF deficits, whereas a response to electroconvulsive therapy was associated with an additional rCBF decrease in the parietotemporal and cerebellar regions bilaterally. Hypoperfusion in major depressive disorder largely normalizes after a response to pharmacotherapy. Perfusion changes after a response to electroconvulsive therapy may follow a different course.