Six chloralose-urethane anesthetized dogs (23 +/- 2 kg) underwent median thoracotomy (open pleural spaces) and constant mechanical ventilation with O2. We conducted measurements at baseline and during 25 min of ventilation with 3.3 cmH2O positive end-expiratory pressure (PEEP3) or 10.7 cmH2O PEEP (PEEP 11), including breath-by-breath values in the first 2 min after PEEP began. PEEP 11 immediately decreased pulmonary CO2 elimination per breath (VCO2,br, digital integration and multiplication of exhaled flow and FCO2) from 8.4 +/- 2.0 to 4.5 +/- 1.6 ml (P < 0.05) by significantly decreasing alveolar ventilation (VA) (29% increase in anatomical dead space (VDana) and generation of high VA/Q regions) and by decreasing alveolar PCO2 (PACO2) from 42.5 +/- 3.5 to 35.9 +/- 3.5 Torr (decreased CO2 transfer to the lung as electromagnetic aortic cardiac output (QT) decreased by 51%). The immediate dilution of alveolar gas and PACO2 by fresh gas as PEEP increased functional residual capacity by 1152 +/- 216 ml was offset by simultaneous decreased expiratory volume and, hence, CO2 accumulation. Compared to baseline, the 17% reduction in VCO2,br was sustained at 25 min after addition of PEEP 11 because VA remained depressed. Then, VCO2,br could only be restored to baseline if PACO2 sufficiently increased. However, CO2 transport was still in unsteady state at 25 min of PEEP. Peripheral tissue retention of CO2 and the significant increase in mixed venous PCO2 (PVCO2, 62.4 +/- 6.2 Torr) were not enough to normalize CO2 transfer to the lung and to sufficiently increase PACO2, especially during the continued depression in QT that occurred at higher PEEP. The sustained decrease in VCO2,br during PEEP was not mirrored by changes in end-tidal PCO2 (PETCO2).