To investigate factors determining the diffusion constant for carbon monoxide (KCO) in normal children, the single breath method was used in 33 healthy children and young adults, 6-30 yr of age. In the sitting position KCO decreased with increasing height (r = -0.59, P < 0.001), suggesting greater recruitment of pulmonary vascular bed at the apexes in the shorter subjects. Increase in the KCO after taking the supine position was significantly less in the shorter subjects (8% at 120 cm) than in the taller subjects (27% at 170 cm), confirming this mechanism. Ten subjects with pulmonary involvement from cystic fibrosis had normal supine KCO but did not show a normal decrease in the upright position. Decrease in the conventionally measured KCO during childhood reflects a gravity-dependent decrease in recruitment of the pulmonary vascular bed and a decrease in the ratio of alveolar surface area to alveolar volume during growth. Diseases associated with hypoxic pulmonary vasoconstriction tend to recruit the pulmonary vascular bed at the apexes, increasing the conventionally measured KCO.