We evaluated whether pituitary-adrenal response to surgical stress is modified in chronic schizophrenic patients. Twenty-two schizophrenic patients on chronic antipsychotic therapy of phenothiazine derivatives over 10 years underwent orthopedic surgery of the extremities under general anesthesia by isoflurane and nitrous oxide. In chronic schizophrenic patients, responses of plasma epinephrine, norepinephrine, ACTH and cortisol levels during surgical stress were significantly lower than those of control patients. The attenuated response to surgical stress in these patients may be associated with their autonomic dysfunction and decreased pituitary-adrenal activity due to chronic administration of antipsychotic agents.