Increased spontaneous activity of the hypothalamic-pituitary-adrenal (HPA)-axis is frequently reported in major depressed inpatients. The aim of the present study was to determine whether there are differences in spontaneous HPA-axis activity between major depressed inpatients and outpatients. Toward this end, the authors measured basal 9:00 a.m. plasma cortisol and the integrated assessment of plasma morning cortisol secretion over 2 (AUC 120) hours in 48 major depressed inpatients, 17 major depressed outpatients and 73 normal volunteers. Major depressed inpatients exhibit significantly higher plasma cortisol values than healthy controls and major depressed outpatients. The cortisol data from the latter are not significantly different from these of the healthy controls. The cortisol differences between in and outpatients were still present after considering the influences of age, sex, body mass index, severity or endogeneity of illness, unipolar/bipolar subclassification, or specific symptoms such as suicidal thoughts, insomnia, psychomotor disorders, psychoticism, weight loss or anxiety. The results indicate that hypercortisolism as measured by basal morning plasma levels is not a feature of major depression per se, but rather of an interaction between the illness and hospitalization.