Extracorporeal CO2 removal may reduce minute ventilation requirements and allow for better tolerance of low tidal volume ventilating strategies in patients with severe respiratory insufficiency. Conventional extracorporeal gas exchange is labor-intensive, expensive, and usually requires systemic anticoagulation. In this study, a simplified venovenous circuit was developed by using regional citrate anticoagulation to avoid potential complications associated with systemic heparin. Five healthy adult sheep underwent percutaneous placement of a double-lumen 18F catheter into the internal jugular vein. The extracorporeal circuit consisted of a hollow fiber oxygenator and a variable speed roller pump. Regional anticoagulation consisted of a continuous citrate infusion to the inflow limb of the circuit. Systemic calcium levels were maintained by calcium chloride infusion through a central line. CO2 transfer was measured at varying levels of blood and gas flow. CO2 transfer ranged from 31 ml/min (500 ml/min blood flow; 2 l/min gas flow) to 150 ml/min (1000 ml/min blood flow; 15 l/min gas flow) and was directly proportional to blood flow and gas flow (p < 0.05). Normocapnia was maintained despite a 75% reduction in minute ventilation. At 24 hours, there was no significant clot formation in the circuit.