Objective: In the vulnerability-stress concept of schizophrenia, schizophrenic patients are thought to display increased sensitivity to stress. Little is known about the biological mechanisms that are involved in stress processing in schizophrenic patients. In this study, hypothalamic- pituitary-adrenal (HPA) function in schizophrenic patients was studied for its essential role in stress processing and adaptation to the environment. Methods: Eighteen schizophrenic patients were compared to 21 healthy controls in their salivary cortisol response to a physical (bicycle ergometry) and a psychosocial (public speaking) stressor. Coping questionnaires were included as a measure of stress processing at the psychological level. Basal HPA function was assessed by measuring cortisol day profiles and feedback activity by using dexamethasone and hydrocortisone. Results: Schizophrenic patients showed blunted cortisol responses to the psychosocial stressor, but not to the physical stressor, in spite of similar increases in heart rate. The cortisol response to the psychosocial stressor tended to be negatively correlated to the use of passive and avoidant coping strategies. Basal HPA function appeared intact in the schizophrenic patients. Conclusions: The findings show a selective impairment in the response to psychosocial stress in schizophrenic patients. This suggests the involvement of brain systems that play a role in the activation of the HPA system to psychosocial stress, like arginin-vasopressin (AVP), and cognitive processes, like coping.