Hormonal and metabolic responses were measured in 15 neonates who underwent repair of complex congenital heart defects during a standardized anesthetic protocol. Four of the 15 neonates died postoperatively in the intensive care unit. Analysis of arterial plasma samples obtained before, during, and 24 h after surgery showed that plasma epinephrine, norepinephrine, cortisol, glucagon, and beta endorphin increased in all patients (P < 0.05). Insulin levels increased only at the end of surgery but remained elevated for 24 h postoperatively (P < 0.02). Intraoperative metabolic changes were characterized by hyperglycemia and lactic acidemia that persisted postoperatively. This pattern of neonatal stress responses is distinct from and more extreme than that seen in adult cardiac surgical patients. The four neonates who died postoperatively tended to have higher stress responses intra- and postoperatively despite having been indistinguishable from survivors by the usual clinical and hemodynamic criteria. These preliminary results suggest that neonatal hormonal and metabolic responses to cardiac surgical operations in neonates are extreme and are associated with a high hospital mortality rate.