A clinical follow-up study was performed of adolescent major depressives and normal control subjects approximately 10 years after the subjects had undergone serial cortisol measurements over a 24-h period. In light of their young adulthood clinical status, our objective was to ascertain whether there were any premorbid cortisol abnormalities associated with depressive course of illness. In all, 77 young adults who had received a diagnosis of adolescent major depressive disorder, or were determined to be normal volunteers free of psychiatric diagnosis at index period and during follow-up, were studied. When subjects were adolescents, blood samples were collected for cortisol at 20-min intervals during the 24-h period coinciding with the third consecutive night of sleep EEG. The subjects, in young adulthood at the time of follow-up, were reinterviewed regarding longitudinal course of illness, and the original adolescent cortisol data were analyzed in the light of information obtained. Of the subjects who had experienced at least one lifetime major depressive episode during the follow-up period, the subgroup who would go on to make suicide attempts during the follow-up period secreted significantly greater levels of cortisol in the 4, 6, and 12 h prior to sleep onset. Conversely, this same subgroup exhibited reduced cortisol levels 2-4 h following sleep onset. Adolescents who are at risk to make suicide attempts appear to display significant elevations of cortisol prior to sleep onset, a time when the hypothalamic-pituitary-adrenal (HPA) axis is normally most quiescent. Dysregulation of the HPA axis, combined with dysfunction of sleep-onset mechanisms previously reported in this same cohort, might serve as premorbid biological substrates that predict suicide attempts during follow-up.