In anesthetized, mechanically ventilated patients, 10 cm H2O positive end-expiratory pressure (PEEP10) immediately decreased the CO2 volume exhaled per breath (V(CO2,br)) by 96%, as exhaled tidal volume (VT) decreased to expand functional residual capacity during the first 8 breaths after PEEP10 began. Then, the sustained decrease in V(CO2,br) for over 10 min was due to the 19% decrease in cardiac output (QT, decreased CO2 delivery from tissues to lung) and to the decrease in alveolar ventilation (VA). In turn, decreased VA resulted from decreased VT (loss of inspired volume into the compressible volume of the ventilating circuit) and possibly from increased physiological dead space, due to the potential for new high alveolar ventilation-to-perfusion (VA/Q) lung regions. V(CO2,br) increased and recovered to baseline by 20 min of PEEP10 ventilation because QT increased to augment the CO2 delivery to the lung and alveolar P(CO2) increased (increased mixed venous P(CO2) and tissue CO2 retention) to increase V(CO2,br) while alveolar VT remained depressed. End-tidal P(CO2) (PET(CO2) progressively increased during PEEP10 and did not detect the decrease in V(CO2,br) during PEEP10 ventilation because PET(CO2) does not account for exhaled volume.