Major depression is characterized by overactivity of the hypothalamic±pituitary±adrenal (HPA) axis. Dexamethasone (DEX), the glucocorticoid agonist, has been shown to be eective in the treatment of depression. We chose to examine the impact of a short course of DEX treatment on depressive symptomatology, and on the pituitary-adrenal response to CRH administration. In this preliminary study, ®ve subjects with major depression were treated for 4 days with 3 mg DEX; a CRH test was performed before and after treatment. Four subjects showed a reduction in ACTH ( p 0 . 01) and cortisol output ( p 5 0 . 01) following DEX treatment. All subjects showed a drop in depression scores after treatment; the Hamilton Depression score fell by 11 . 4+1 . 7 (mean+SEM) from baseline ( p 0 . 01) and the Beck Depression score by 9 . 2+2 . 5 (mean+SEM) from baseline ( p 0 . 01); this represented a reduction by almost 50 per cent from baseline levels on both depression indices. We suggest that the impact of DEX treatment on depressive symptoms may re¯ect a restraining in¯uence on an overactive HPA, with a normalization of pituitary± adrenal response to CRH drive. Larger studies are required to investigate this further and to ascertain whether the mood and neuroendocrine changes induced by dexamethasone are sustained.