The problem faced in determining the ventilatory response to CO2 near eupnea has been the difficulty of unloading metabolically produced CO2 from the subject in the steady state. Previous methods using extracorporeal circuits to unload CO2 are technically difficult and provide a limited number of experimental states per experiment. Using the method of high-frequency ventilation to unload CO2, we were able to obtain a large number of determinations in the same subject under conditions of hypoxia, normoxia, and hyperoxia. Data collected in five awake dogs show that the ventilatory response to CO2 is linear down to apnea during normoxic conditions but exhibits nonlinear behavior dependent on the level of arterial O2 tension. During hyperoxic conditions, the response was concave curvilinear, with a statistically significant decrease in slope near apnea. In contrast, mild hypoxia led to a convex curvilinear response with an increased slope near apnea.