OBJECTIVE: Current hypotheses hold that mechanisms underlying abnormal hypothalamic-pituitary-adrenocortical (HPA) function are causal factors in the precipitation of depression. If this is the case, then normalization of initially disturbed HPA regulation should indicate a good prognosis and persistent HPA dysregulation should be associated with a greater likelihood of relapse or chronicity. METHOD: The combined dexamethasone/corticotropin-releasing hormone test was administered twice to inpatients with major depression (N=40), once after initiation of treatment and once after remission, shortly before discharge. RESULTS: Patients with a high cortisol response on both occasions or with a substantially increased cortisol response at discharge were at much higher risk for relapse within the next 6 months than those with low cortisol responses. CONCLUSIONS: An easy-to-administer neuroendocrine test allows the prediction of medium-term outcome in patients with remitted depression.