Sixty-one dextral, unmedicated women with chronic fatigue syndrome (CFS) diagnosed according to the Fukuda criteria (1994) and referred for investigation by rheumatologists and internists were studied with quantitative EEG (43 channels) at rest with eyes open and during verbal and spatial cognitive activation. The EEGs from the patients were compared with recordings from 80 dextral healthy female controls. Only those subjects who could provide 20 1-s artefact-free segments of EEG were admitted into the study. The analysis consisted of the identification of the spatial patterns in the EEGs that maximally differentiated the two groups and the estimation of the cortical source distributions underlying these patterns. Spatial patterns were analyzed in the alpha (8–13 Hz) and beta (14–20 Hz) bands and the source distributions were estimated using the Borgiotti–Kaplan BEAMFORMER algorithm. The results indicate that the spatial patterns identified were effective in separating the two groups, providing a minimum correct retrospective classification rate of 72% in both frequency bands while the subjects were at rest to a maximum of 83% in the alpha band during the verbal cognitive condition. Underlying cortical source distributions showed significant differences between the two groups in both frequency bands and in all cognitive conditions. Lateralized cortical differences were evident between the two groups in the both frequency bands during both the verbal and spatial cognitive conditions. During these active cognitive conditions, the CFS group showed significantly greater source-current activity than the controls in the left frontal–temporal–parietal regions of the cortex.