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Background: A critical parameter of extracorporeal CO2 removal (ECCO2R) applications is the CO2 removal rate (VCO2). Low‐flow venovenous extracorporeal support with large‐size membrane lung remains undefined. This study aimed to evaluate the VCO2 of a low‐flow ECCO2R with large‐size membrane lung using a renal replacement therapy platform in an experimental animal model. Methods: Twelve healthy pigs were placed under mechanical ventilation and connected to an ECCO2R‐CRRT system (surface area = 1.8 m2; OMNIset®, BBraun, Germany). Respiratory settings were reduced to induce two degrees of hypercapnia. VCO2 was recorded under different combinations of PaCO2 (50–69 or 70–89 mm Hg), extracorporeal blood flow (ECBF; 200 or 350 mL/min), and gas flow (4, 6, or 10 L/min). Results: VCO2 increased with ECBF at all three gas flow rates. In severe hypercapnia, the increase in sweep gas flow from 4 to 10 L/min increased VCO2 from 86.38 ± 7.08 to 96.50 ± 8.71 mL/min at an ECBF of 350 mL/min, whereas at ECBF of 200 mL/min, any increase was less effective. But in mild hypercapnia, the increase in sweep gas flow result in significantly increased VCO2 at two ECBF. VCO2 increased with PaCO2 from 50–69 to 70–89 mm Hg at an ECBF of 350 mL/min, but not at ECBF of 200 mL/min. Post‐membrane lung PCO2 levels were similar for different levels of premembrane lung PCO2 (p = 0.08), highlighting the gas exchange diffusion efficacy of the membrane lung in gas exchange diffusion. In severe hypercapnia, the reduction of PaCO2 elevated from 11.5% to 19.6% with ECBF increase only at a high gas flow of 10 L/min (p < 0.05) and increase of gas flow significantly reduced PaCO2 only at a high ECBF of 350 mL/min (p < 0.05). Conclusions: Low‐flow venovenous extracorporeal ECCO2R‐CRRT with large‐size membrane lung is more efficient with the increase of ECBF, sweep gas flow rate, and the degree of hypercapnia. The influence of sweep gas flow on VCO2 depends on the ECBF and degree of hypercapnia. Higher ECBF and gas flow should be chosen to reverse severe hypercapnia. [ABSTRACT FROM AUTHOR]