The possible role of intrapulmonary CO2 receptors (IPC) in arterial CO2 partial pressure (PaCO2) homeostasis was investigated by comparing the arterial blood gas and ventilatory responses to CO2 loading via the inspired gas and via the venous blood. Adult male Pekin ducks were decerebrated 1 wk prior to an experiment. Venous CO2 loading was accomplished with a venovenous extracorporeal blood circuit that included a silicone-membrane blood oxygenator. The protocol randomized four states: control (no loading), venous CO2 loading, inspired CO2 loading, and venous CO2 unloading. Intravenous and inspired loading both resulted in hypercapnic hyperpnea. Comparison of the ventilatory sensitivity (delta VE/delta PaCO2) showed no significant difference between the two loading regimes. Likewise, venous CO2 unloading led to a significant hypocapnic hypopnea. Sensitivity to changes in PaCO2 could explain the response of ventilation under these conditions. The ventilatory pattern, however, was differentially sensitive to the route of CO2 loading; inspired CO2 resulted in slower deeper breathing than venous loading. It is concluded that IPC play a minor role in adjusting ventilation to match changes in pulmonary CO2 flux but rather are involved in pattern determination.