The purpose of this study was to determine whether the transfer function characteristics of the respiratory CO2 control system differs according to whether the CO2 administration method is constant fraction (CF) or constant inflow (CFlow). Ventilatory responses to CO2 changes were measured in seven healthy subjects during random PETCO2 perturbation by the CF and CFlow administration methods in normoxia and hyperoxia. The transfer function from PCO2 to VE was estimated in the frequency domain from 0.002 to 0.02 Hz. The transfer function characteristics showed a low-pass filter character in both of CFlow and CF. The impulse responses to both the methods persisted for > or = 60 sec, while the maximum amplitude (hmax) of the CFlow response was statistically greater than that of the CF response in normoxic condition. The time required until the peak (tmax) of the CFlow impulse response was shorter than that of CF in normoxia. Hyperoxia retarded the tmax and reduced hmax in both CFlow and CF, with the result that significant differences in the normoxic impulse responses were not observed between CFlow and CF in hyperoxia. To characterize the CO2 control system quantitatively, we determined the static transfer gain, oscillatory frequency, damping factor, and pure time delay by applying a second-order delay model to the observed transfer function. The static gain was not significantly different between CFlow and CF responses in both normoxia and hyperoxia. The pure time delay and damping factor were significantly decreased for CFlow only in normoxia. We suggest that inhalation of CO2 by CFlow modifies ventilatory response, probably mediating through the peripheral chemoreceptor activity.