The reactivity of the hypothalamic-pituitary-adrenal (HPA) axis was investigated in 10 female patients fulfilling the Yunus criteria for the primary fibromyalgia syndrome (PFS) and in 10 matched, healthy and sedentary controls. The 2 groups were subjected to a dexamethasone suppression (DXM) test, a corticotropin-releasing hormone (CRH) test and an insulin induced hypoglycemia (IH) test. In the DXM test there was no escape from suppression in patients or controls. The CRH and the IH tests showed a markedly enhanced, and statistically significant, adrenocorticotropic hormone (ACTH) release in patients with PFS versus controls, while the cortisol response in both groups was not different. Our data suggest that fibromyalgia is related to a neuroendocrine disorder characterized by hyperreactive pituitary ACTH release and a relative adrenal hyporesponsiveness. This HPA response pattern is unique and contrasts to the hypercortisolemic responses observed in affective disorders, e.g., depression, which like PFS, are often thought to be precipitated by chronic stress. Our findings seem to indicate a relative adrenal insufficiency in PFS, which might serve clinically as an explanation for the reduced aerobic capacity and impaired muscle performance these patients display.