The time course of the transient ventilatory response to a sudden change in Inspired gas from room air to 4% CO2in air was examined in 11 healthy preterm neonates. Changes in minute ventilation (&OV0312;1), tidal volume (VT), and respiratory frequency (f) were determined over 4 to 5 min of CO2inhalation during both quiet (QS) and active sleep (AS) in each infant. In both states there was a brisk increase of mean &OV0312;1in response to 4% CO2, while mean VTincreased more slowly and mean f only increased transiently at 1 to 2 min. Exponential curve fitting to the change in Vi and VT for each infant accounted for 64 ± 20% of the variance in Vi during QS as compared to 30 ± 18% during AS (p<0.003). In only six infants did exponential curves fitted to the changes in &OV0312;1and VT during QS reach 90% of their steady state values within 4 to 5 min of CO2exposure. Their time to reach 90% of steady state was always shorter for &OV0312;1than VT (p<0.01). Frequency showed a biphasic response with a transient rise at 1 to 2 min (p<0.05) and return to control levels at steady state. These data indicate that not all preterm infants reach a new level of steady state ventilation within 4 to 5 min of 4% CO2inhalation. Furthermore, many infants exhibit a biphasic response of f over time which causes &OV0312;1to reach steady state prior to VT.