In older children and adults, physiologic instability associated with severe illness causes increased cellular oxygen consumption (Vo2), increased serum lactate and cortisol levels, and more negative nitrogen balance. To determine the metabolic response of preterm infants to severity of respiratory illness, we analyzed Vo2, nitrogen balance, urinary 3-methyl-histidine and norepinephrine concentrations, and serum levels of lactate and cortisol as a function of ventilatory index (VI). Twelve 2-day-old premature infants who were appropriate in size for gestational age (mean ± SEM birth weight: 1460 ± 251 gm) and who required mechanical ventilation for respiratory distress syndrome had Vo2 and carbon dioxide production measured by indirect calorimetry and blood and urine samples obtained concurrently. All infants received amino acids, 1.0 gm/kg per day, and a mean energy intake of 27 ± 3 kcal/kg per day, provided as a parenteral dextrose solution. The resting energy expenditure exceeded energy intake in all infants. The Vo2 value ranged from 5.5 to 9.2 ml/kg per minute and was directly correlated with VI (r = 0.79; p = 0.002). Nitrogen balance ranged from -160 to 53 mg/kg per day (mean: -33 ± 21 mg/kg per day) but was not dependent on VI (r = 0.04) or Vo2 (r = 0.01). The serum lactate level correlated directly with VI (r = 0.82; p = 0.002) and Vo2 (r = 0.60; p = 0.05), but cortisol and urinary norepinephrine levels did not. We conclude that preterm infants with respiratory distress syndrome have increased Vo2 rates and serum lactate concentrations directly related to the degree of respiratory illness. They are generally in a state of mildly negative nitrogen balance, the degree of which is not related to severity of illness. Although these infants may require increased energy delivery during illness, they do not appear to require excessive amounts of amino acids. (J PEDIATR 1994;124:283-8).