The objective of this study was to investigate the relationship between the effect of sleep deprivation, recovery and regional brain perfusion in patients with major depression. Regional cerebral blood flow was assessed by 99mTc-HMPAO-SPECT before and after sleep deprivation in fourteen medicated patients. Three of the patients underwent a follow-up measurement after clinical recovery and with an unchanged antidepressant medication. Before sleep deprivation the responding patients had a significantly higher anterior cingulate perfusion than the nonresponding patients, that normalized after sleep deprivation. Cingulate perfusion uniquely differentiated eventual treatment response from non-responders, as perfusion in no other region under study discriminated the two groups. At baseline all patients revealed hypoperfusion in the left prefrontal cortex when compared to the right side, which was not affected by sleep deprivation, whereas prefrontal hypoperfusion was reversible upon remission. These findings are in agreement with previous PET investigations and provide evidence for cingulate and prefrontal dysfunction associated with depression, that are reversible by successful treatment and may represent state markers.