Ventilatory response during external dead space (tube) breathing and CO2 inhalation for given increase in PETCO2 were compared at different levels of PETO2 (hyperoxia, normoxia, and hypoxia) in human subjects. At all the PETO2 levels studied, magnitude of increment in minute ventilation (VE) and tidal volume were larger in the dead space breathing than in the CO2 inhalation. The slope of CO2-ventilation response line was significantly steeper in the dead space breathing only in the hypoxic condition. There was no significant difference in frequency response to CO2 between the two methods. These results suggested that augmented ventilatory response to CO2 in the dead space breathing occurs in the condition of peripheral chemoreceptor activation.