The purpose of this study was to determine oxygen consumption (VO 2 ), carbon dioxide production (VCO 2 ), and energy expenditure (EE) in a group of preterm ventilated infants during the first 3 weeks of life, and to determine the major factors that influence EE. Thirty-eight indirect calorimetry studies were performed in 18 ventilated infants with mean gestational age of 27.9 ± 0.6 (SEM) weeks. The relationship of demographic factors, nutrient intake, and severity of illness assessments on EE were determined by regression analysis. Repeated measure analysis was performed for the effect of multiple studies in the same patient. Although VO 2 , VCO 2 , and EE all tended to increase over the first 3 weeks of life, there was a wide range of values. EE was best predicted by non-protein calorie intake and postnatal age, while there was no correlation with birthweight, weight at the time of study, gestational age, protein intake, or severity of illness. Multiple regression analyses demonstrated a strong interaction between PNA and EI. In this population EE is best predicted by PNA and EI. The interactive effect between PNA and EI on EE is probably explained by the clinical practice of daily increments in substrate intake in these patients.