An explorative analysis of the relationship between symptomatology and cerebral blood flow in the chronic fatigue syndrome (CFS) as assessed with 99mTc HMPAO SPECT scan reveals statistically significant positive correlations between frontal blood flow on the one hand and objectively and subjectively assessed cognitive impairment, self-rating of physical activity limitations and total score on Hamilton Depression Rating Scale on the other. A pathophysiological role of frontal blood flow in the cognitive impairment and physical activity limitations in CFS is hypothesized. A comparison of cerebral blood flow between CFS, major depression (MD) and healthy controls (HC) has been performed. A lower superofrontal perfusion index is demonstrated in MD as compared with both CFS and HC. There is neither a global nor a marked regional hypoperfusion in CFS compared with HC. Asymmetry (R > L) of tracer uptake at parietotemporal level is demonstrated in CFS as compared with MD.