BACKGROUND: A dysregulation in the hypothalamic-pituitary-adrenal (HPA)-axis function has been repeatedly observed in major depressive disorders (MDD). Normalization of this dysregulation, i.e. of cortisol suppression after glucocorticoid receptor (GR)-stimulation, may be mandatory for clinical remission in some patient subgroups. However, there are no biological measures applied in the clinical setting to identify patient subgroups with HPA axis alterations. OBJECTIVE: We aimed to define a suppression index of cortisol concentrations before and after GR stimulation with dexamethasone to predict the variability in improvement of HPA axis activity during antidepressant treatment. METHODS: A modified dexamethasone suppression test (mDST) was performed with blood withdrawal for cortisol and ACTH measurement before and 3 h after 1.5 mg dexamethasone intake at 18:00 in two cohorts of depressed patients treated in a naturalistic setting. The discovery sample consisted of 106 patients, the replication sample of 117 patients. The suppression index was defined as cCORTpreDEXcCORTpostDEX. RESULTS: The baseline suppression index explained 27.4 % of the variance in changes of HPA axis activity before and after treatment with antidepressants. Age, cCORTpreDEXcACTHpreDEX at baseline and sex explained further variance up to 56.2 % (stepwise linear regression, p = 7.8e-8). A threshold of the suppression index at baseline was determined by ROC analysis and revealed, that only patients with a maximum index of 2.32 achieved a normalization of the HPA axis activity after antidepressant treatment. In the replication sample, the threshold was 2.86. However, the estimated suppression index was not associated with treatment response. CONCLUSION: For the first time, by establishing a short-term suppression index of cortisol before and after GR-stimulation a threshold could be identified to predict improvement of HPA axis activity during antidepressant therapy. After replication in further studies this index may help to identify patients who benefit from a specific treatment that targets components of the HPA axis in the future.