The respiratory response to CO2 during pressure-support ventilation (PSV) was studied in 16 conscious normal humans. The subjects breathed through a mouthpiece connected to a ventilator in PSV mode, with pressure set to the highest comfortable level for each subject (10.1 +/- 0.6 cm H2O, mean +/- SE). Compared with breathing spontaneously through the ventilator (CPAP mode with zero positive end-expiratory pressure), with PSV, tidal volume (VT) increased significantly (1.16 +/- 0.1 versus 0.85 +/- 0.04 L), whereas breathing frequency (f) remained stable (16.0 +/- 0.9 versus 15.6 +/- 1.1 breaths/min). As a result, the subjects hyperventilated, decreasing significantly end-tidal PCO2 (PETCO2, 23.5 +/- 1.2 versus 35.5 +/- 1.1 mm Hg). Fraction of inspired CO2 (FICO2) was then increased in steps, and changes in respiratory motor output were quantitated from changes in f, VT, ventilation (VI), peak inspiratory flow (Vpeak), and muscle pressure (Pmus). Pmus was calculated by the equation of motion, based on respiratory system mechanics, which were measured previously by airway occlusion at end-inspiration, VT, VI, and Pmus increased significantly with increasing PETCO2, and the response was detectable even below eupneic levels; f remained relatively stable over a wide range of PETCO2 (23 to 45 mm Hg) and increase significantly only when PETCO2 approached 50 mm Hg. These results indicate that in conscious normal humans during PSV, CO2 responsiveness extends well into hypocapnia and is expressed principally as an increase in intensity of respiratory motor output with little change in respiratory rate.