We demonstrated pulmonary arteriolar blood flow-mediated CO₂ gas excretion in rabbit lungs. The shear stress stimulation produced CO₂ gas in cultured human endothelial cells of pulmonary arterioles via the activation of F₁/F_o ATP synthase. To confirm the findings in human subjects undergoing the operation with heart–lung machines, we aimed to evaluate the effects of a stepwise switch, from a partial to a complete cardiopulmonary bypass, of the circulatory blood volume (BV, 100% = 2.4 × cardiac index), on the end-expiratory CO₂ pressure (PetCO₂), maximal flow velocity in the pulmonary artery (Max Vp), the inner diameter (ID) of pulmonary artery, pulmonary arterial CO₂ pressure (P mix v CO₂), pulmonary arterial O₂ pressure (P mix v O₂), hematocrit (Hct), pH, the concentration of HCO₃⁻, and base excess (BE) in mixed venous blood in 9 patients with a mean age of 72.3 ± 3.4 years. In addition, the effects of the decrease in Hct infused with physiological saline solution (PSS) on PetCO₂ were investigated in the human subjects. An approximately linear relationship between the PetCO₂ and Max Vp was observed. The pumping out of 100% BV produced little or no change in the Hct, pH, P mix v CO₂, and P mix v O₂, respectively. The hemodilution produced by intravenous infusion of PSS caused a significant decrease in the Hct, but not in the PetCO₂. In conclusion, another route of CO₂ gas excretion, independent of red blood cells, may be involved in human lungs.