Our hypothesis was that surfactant instilled into the trachea, followed by body positioning maneuvers utilized to enhance drug distribution, could alter hemodynamic function and stimulate the release of catecholamines. We conducted a prospective randomized study designed to compare the immediate physiologic effects of the first dose of Exosurf Neonatal (5 mL/kg; n = 16) or Survanta (4 mL/kg; n = 18), when surfactant administration was standardized with strict adherence to drug company protocol. Physiologic variables were monitored continuously. Arterial blood gases (ABG) and plasma catecholamine concentrations were measured before, and 5 minutes after, surfactant administration. Both surfactants had an immediate effect on arterial oxygen saturation (SaO2), partial pressure of oxygen in arterial blood (PaO2), and oxygen index (OI). The improvement in oxygenation after surfactant therapy was similar in both groups. There was no significant difference in the mean umbilical arterial blood pressure (ABP) following surfactant therapy in both groups. High concentrations of plasma norepinephrine (reflecting activity of the sympathetic nerves) and epinephrine (a measure of secretion from the adrenal medulla) indicate that preterm infants with respiratory distress syndrome (RDS) prior to treatment mount a substantial stress response. The currently recommended techniques for instillation of surfactant appear not to trigger a significant further surge of plasma catecholamines or to acutely change mean ABP. Alternatively, it may be possible that the lack of response was because catecholamine release was already maximal.