Increased awareness of pressure-related injury to the alveolar-capillary interface has renewed interest in modes of ventilation that limit alveolar distention such as pressure-controlled ventilation (PCV). We examined respiratory system mechanics and gas exchange during PCV in six dogs. Our data conformed to the predictions of our single-compartment mathematical model of respiratory dynamics during PCV (J Appl Physiol 1989; 67:1081-92). For a fixed pressure (Pset) and inspiratory time fraction (TI/Ttot) (15 cm H2O and 0.3, respectively), minute ventilation (V̇E) reached a well-defined plateau as frequency (f) increased from 10 to 50 breaths/min and tidal volume (VT) fell progressively. Concomitantly, the physiologic dead-space fraction (VD/VT) increased from 0.50 ± 0.04 to 0.85 ± 0.04, and arterial P(CO2) (Pa(CO2)) rose from 39 ± 4 to 76 ± 12 mm Hg. At a fixed combination of frequency, applied pressure, and TI/Ttot (40 breaths/min, 15 cm H2O, and 0.3), V̇E did not change when we introduced fresh gas continuously from an intratracheal catheter. However, Pa(CO2) and VD/VT fell progressively as catheter flow increased from zero to 14 L/min (60 ± 12 to 40 ± 12 mm Hg and 0.83 ± 0.03 to 0.25 ± 0.14 mm Hg, respectively). We conclude that during PCV at a fixed Pset and TI/Ttot increasing frequency caused VT to fall and V̇E to reach a plateau. Declining VT was associated with a rise in Pa(CO2) because of a subsequent fall in alveolar ventilation. Insufflating fresh gas by an intratracheal catheter increased alveolar ventilation and improved CO2 elimination by washing out the anatomic dead space. These results suggest that such techniques may be a useful clinical adjunct to conventional mechanical ventilation.