The human response to surgical stress is characterized by massive release of neuroendocrine hormones, provoking catabolism, thermogenesis, and hyperglycemia. Considering the possible adverse outcomes of excessive stress hormones, understanding various components of the stress response may improve management of postoperative morbidity. Leptin, initially described as an adipocyte-derived signaling factor, may also play an important role in regulating the hypothalamo-pituitary-adrenocortical axis. In phase I, plasma leptin and cortisol were measured in women before, during, and after total abdominal hysterectomy. The anesthetic technique was strictly controlled, balanced anesthesia. In phase II, plasma leptin and cortisol levels were measured in cardiac surgery patients. These subjects were anesthetized with a high dose opioid technique that blunts the intraoperative surgical stress response. In phase I, mean leptin levels did not change over the week before surgery, had a maximal decrease to 49% of baseline 2 h after surgery, and increased to just above baseline 24 h postoperatively. Cortisol was 176% of the baseline just before surgery, peaked at 2 h after surgery (383%), and remained elevated 24 h (200%) and 48 h (165%) after surgery. During the first 2 h of surgery, the decrease in leptin parallels the increase in cortisol. In phase II, high dose fentanyl limited both the cortisol increase and the leptin decrease; thus, the ratio of cortisol increase to leptin decrease was similar for the cardiac patients and the hysterectomy patients. These data indicate that leptin has a role in the surgically induced acute stress response in humans. Early in surgery the decrease in leptin parallels the increase in cortisol. This suggests a possible relationship between the neurobiology of these two systems, which could have important implications for regulation of the neuroendocrine response to surgical stress.