Summary In man assuming the upright position, end-tidal PCO₂ (PETCO₂) decreases. With the rising interest in cerebral autoregulation during posture change, which is known to be affected by PETCO₂, we sought to determine the factors leading to hypocapnia during standing up from the supine position. To study the contribution of an increase in tidal volume (VT) and breathing frequency, a decrease in stroke volume (SV), a ventilation-perfusion (V/Q) gradient and an increase in functional residual capacity (FRC) to hypocapnia in the standing position we developed a mathematical model of the lung to follow breath-tobreath variations in PETCO₂. A gravity-induced apical to basal V/Q gradient in the lung was modelled using 9 lung segments. We tested the model using an eight-subject data set with measurements of VT, pulmonary O₂ uptake and breath-to-breath lumped SV. On average, the PETCO₂ decreased from 40 mmHg to 36 mmHg after 150 s standing. Results show that the model is able to track breath-to-breath PETCO₂ variations (r² = 0.74, p<0.05). Model parameter sensitivity analysis demonstrates that the decrease in PETCO₂ during standing is due primarily to increased VT and transiently, decreased SV and increased FRC; a slight gravity-induced V/Q mismatch also contributes to the hypocapnia. The influence of cardiac output on hypocapnia in the standing position was verified in experiments on human subjects, where first breathing alone, then breathing, FRC and V/Q were controlled.