The relationship between neuropsychological test performance and regional cerebral blood flow (rCBF) was examined in 29 patients meeting Research Diagnostic Criteria (RDC) for major depression. Following a comprehensive neuropsychological assessment two subsets of tests, comprising tests that discriminated between patients and controls or between patients with varying degrees of global cognitive impairment, were selected. These subtests were entered into a principal components analysis (PCA) which generated a two-factor solution, accounting for 50% of the overall variance in test scores. Individual patient loadings on each of these factors were subsequently correlated with regional cerebral blood flow (rCBF), as measured by positron emission tomography (PET). Both factors demonstrated significant correlations with rCBF in the medial prefrontal cortex and frontal polar cortex while for each factor there were also unique patterns of correlations with posterior brain regions. The findings provide additional evidence that neuropsychological deficits in depression are associated with abnormalities in regional brain function and in particular with the function of the medial prefrontal cortex.