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Abstract Background Extracorporeal carbon dioxide removal (ECCO2R) systems have gained clinical appeal as supplemental therapy in the treatment of acute and chronic respiratory injuries with low tidal volume or non-invasive ventilation. We have developed an ultra-low-flow ECCO2R device (ULFED) capable of operating at blood flows comparable to renal hemodialysis (250 mL/min). Comparable operating conditions allow use of minimally invasive dialysis cannulation strategies with potential for direct integration to existing dialysis circuitry. Methods A carbon dioxide (CO2) removal device was fabricated with rotating impellers inside an annular hollow fiber membrane bundle to disrupt blood flow patterns and enhance gas exchange. In vitro gas exchange and hemolysis testing was conducted at hemodialysis blood flows (250 mL/min). Results In vitro carbon dioxide removal rates up to 75 mL/min were achieved in blood at normocapnia (pCO2 = 45 mmHg). In vitro hemolysis (including cannula and blood pump) was comparable to a Medtronic Minimax oxygenator control loop using a time-of-therapy normalized index of hemolysis (0.19 ± 0.04 g/100 min versus 0.12 ± 0.01 g/100 min, p = 0.169). Conclusions In vitro performance suggests a new ultra-low-flow extracorporeal CO2 removal device could be utilized for safe and effective CO2 removal at hemodialysis flow rates using simplified and minimally invasive connection strategies.