Using positron emission tomography (PET) and 15Oxygen, regional cerebral blood flow (rCBF) was measured in 33 patients with primary depression, 10 of whom had an associated severe cognitive impairment, and 23 age-matched controls. PET scans from these groups were analysed on a pixel-by-pixel basis and significant differences between the groups were identified on Statistical Parametric Maps (SPMs). In the depressed group as a whole rCBF was decreased in the left anterior cingulate and the left dorsolateral prefrontal cortex (P < 0·05 Bonferroni-corrected for multiple comparisons). Comparing patients with and without depression-related cognitive impairment, in the impaired group there were significant decreases in rCBF in the left medial frontal gyrus and increased rCBF in the cerebellar vermis (P < 0·05 Bonferroni-corrected). Therefore an anatomical dissociation has been described between the rCBF profiles associated with depressed mood and depression-related cognitive impairment. The pre-frontal and limbic areas identified in this study constitute a distributed anatomical network that may be functionally abnormal in major depressive disorder.