: There are a few reports that chronic fatigue syndrome (CFS) may be accompanied by changes in hormones, such as dehydroepiandrosterone (DHEA) and insulin-like growth factor (IGF1). This study examines the serum concentrations of DHEA-sulfate (DHEAS), IGF1 and IGF1 binding protein-3 (IGFBP3) in 20 patients with CFS and in 12 normal controls. The IGFBP3/IGF1 ratio was computed as an index for IGF1 availability. We found significantly lower serum DHEAS concentrations in CFS, but no significant differences either in IGF1 or the IGFBP3/IGF1 ratio between CFS patients and normal controls. The decrease in serum DHEAS was highly sensitive and specific for CFS. There were significant and positive correlations between serum DHEAS and serum zinc and the mitogen-induced expression of the CD69 molecule on CD3+CD8+ T cells (an indicator of early T cell activation). There was a significant and negative correlation between serum DHEAS and the increase in the serum alpha-2 protein fraction (an inflammatory marker). Serum IGF1, but not DHEAS, was significantly and inversely correlated to age. The results show that CFS is accompanied by lowered levels of DHEAS and that the latter may play a role in the immune (defect in the early activation of T cells) and the inflammatory pathophysiology of CFS.