To prove the hypothesis of a common defect in the central nervous system and immune system in patients with major depression, we examined the inhibition of phytohemagglutinin (PHA)-induced lymphocyte proliferation by in vitro and in vivo administration of glucocorticoids in 20 patients with major depression. The patients were divided into two groups according to the results of the dexamethasone suppression test (DST). Six patients showed cortisol non-suppression. They had significantly higher baseline plasma cortisol levels in comparison with cortisol suppressors. The lymphocytes from cortisol non-suppressors were significantly stronger inhibited by in vitro administration of glucocorticoids compared to the lymphocytes from cortisol suppressors. However, there were no significant differences of lymphocyte inhibition by in vivo administration of glucocorticoids between both patient groups. From our results we conclude that cortisol non-suppressors reveal impaired down-regulation of glucocorticoid receptors of lymphocytes. Furthermore, the effect of glucocorticoids on lymphocyte reactivity may reflect the effects on brain structures in patients with major depression.