This study evaluated the interaction between respiratory chemical drive and non-chemical factors related to the frequency and level of thoracic displacement during mechanical ventilation in shaping respiratory activity. Ten normal subjects were artificially hyperventilated with a positive-pressure mechanical respirator to a baseline end-tidal PCO2 of approximately 30 Torr. Thereafter, in separate trials, the end-tidal PCO2 was increased by (a) progressively raising the concentration of CO2 in the inspired gas (FICO2) while holding tidal volume (VT) and breathing frequency (f) constant, (b) lowering f while holding VT and FICO2 constant, and (c) lowering VT while maintaining a constant f and FICO2. Initially, as the PCO2 rose above baseline levels with increases in FICO2, there was no change in inspiratory muscle activity, as measured by the peak inspiratory airway pressure, until the PCO2 reached 40 Torr. This PCO2 threshold for a change in respiratory activity was significantly reduced when the tidal volume or frequency of mechanical ventilation was lowered. These results suggest that non-chemical drives related to the frequency and level of thoracic displacement interact with chemical stimuli in shaping respiratory activity.