Our objective was to assess the relationship between the pre-/post-oxygenator gradient of the partial pressure of carbon dioxide (∆_EC PCO₂; dissolved form) and CO₂ elimination under extracorporeal respiratory support. All patients who were treated with veno-venous extracorporeal membrane oxygenation and high-flow extracorporeal CO₂ removal in our intensive care unit over 18 months were included. Pre-/post-oxygenator blood gases were collected every 12 h and CO₂ elimination was calculated for each pair of samples (pre-/post-oxygenator total carbon dioxide content in blood [_ctCO₂] × pump flow [extracorporeal pump flow {Q_EC}]). The relationship between ∆_EC PCO₂ and CO₂ elimination, as well as the origin of CO₂ removed. Eighteen patients were analyzed (24 oxygenators and 293 datasets). Each additional unit of ∆_EC PCO₂ × Q_EC was associated with an increase in CO₂ elimination of 5.2 ml (95% confidence interval [CI], 4.7−5.6 ml; p < 0.001). Each reduction of 1 ml STPD/dl of CO₂ across the oxygenator was associated with a reduction of 0.63 ml STPD/dl (95% CI, 0.60−0.66) of CO₂ combined with water, 0.08 ml STPD/dl (95% CI, 0.07−0.09) of dissolved CO₂, and 0.29 ml STPD/dl (95% CI, 0.27−0.31) of CO₂ in erythrocytes. The pre-/post-oxygenator PCO₂ gradient under extracorporeal respiratory support is thus linearly associated with CO₂ elimination; however, most of the CO₂ removed comes from combined CO₂ in plasma, generating bicarbonate.