Inadequate suppression of plasma cortisol after 1–2 mg dexamethasone is frequently observed in depressive patients. To further investigate the pathophysiology underlying cortisol nonsuppression after dexamethasone we compared cortisol and corticotropin (ACTH) response to human corticotropin-releasing factor (h-CRF), lysine vasopressin (LVP), and a concurrent administration of both peptides after pretreatment with 1.5 mg dexamethasone in six male controls. Neither h-CRF nor LVP were able to produce a marked elevation of dexamethasone suppressed plasma cortisol and ACTH. If both peptides were administered in combination, a substantial escape of plasma cortisol from dexamethasone suppression was observed. ACTH responses changed in concordance with those of cortisol indicating that the LVP-CRF interaction takes place at the pituitary level. Our finding is consistent with a multihormonal control of pituitary-adrenal activity and bears several implications for interpretation of dexamethasone suppression test results in depressive illness.