Body water compartment changes were assessed during postnatal weight loss in 14 infants with respiratory distress syndrome. Total body water and extracellular volume were measured by dilution methods on the first day of life and again between the third and sixth days of life. Extracellular volume changes were calculated between the first and second determinations by measurement of chloride balance. Fluid therapy was prescribed to allow negative net water balance and a 1% to 3% reduction in body weight per day. All infants had concurrent reductions in body weight, total body water, and extracellular volume. Progressive daily extracellular volume reduction concurrent with weight loss was also apparent from chloride balance data. The correlation of changes in body weight with extracellular volume in individual subjects was poor (r = 0.05). We speculate that variations between sodium and free water balance in the sick preterm infant may be responsible for variability in the distribution of postnatal body water losses. Assessment of hydration in the newborn infant should include consideration of sodium balance and alterations of serum osmolality, and changes in body weight.