In order to investigate one aspect of cortical-autonomic control, cortical activation asymmetries, measured by EEG, were related to activity of the sympathetic nervous system, measured by EDA (electrodermal lability, number of spontaneous fluctuations), in two large samples. Since it may help to explain the participation of psychological factors in the development of various somatic complaints and disorders, we examined whether inter-individual differences in autonomic nervous system regulation may exist that are related to stress/anxiety and depression within the normal range. Results demonstrate substantial modifications of functional hemisphere asymmetries in the modulation of EDA by these emotional factors and suggest that activation asymmetries in orbital and dorsolateral frontal regions reflect two different cortical sub-systems regulating electrodermal activity. The findings may, to some extent, provide an explanation for contradictory results in previous studies and may encourage research in psychosomatics and other clinical fields (e.g. schizophrenia).