Rationale: In the EOLIA (ECMO to Rescue Lung Injury in Severe ARDS) trial, oxygenation was similar between intervention and conventional groups, whereas [Formula: see text]e was reduced in the intervention group. Comparable reductions in ventilation intensity are theoretically possible with low-flow extracorporeal CO(2) removal (ECCO(2)R), provided oxygenation remains acceptable. Objectives: To compare the effects of ECCO(2)R and extracorporeal membrane oxygenation (ECMO) on gas exchange, respiratory mechanics, and hemodynamics in animal models of pulmonary (intratracheal hydrochloric acid) and extrapulmonary (intravenous oleic acid) lung injury. Methods: Twenty-four pigs with moderate to severe hypoxemia (Pa(O(2)):Fi(O(2))  ⩽  150 mm Hg) were randomized to ECMO (blood flow 50-60 ml/kg/min), ECCO(2)R (0.4 L/min), or mechanical ventilation alone. Measurements and Main Results: [Formula: see text]o(2), [Formula: see text]co(2), gas exchange, hemodynamics, and respiratory mechanics were measured and are presented as 24-hour averages. Oleic acid versus hydrochloric acid showed higher extravascular lung water (1,424 ± 419 vs. 574 ± 195 ml; P < 0.001), worse oxygenation (Pa(O(2)):Fi(O(2)) = 125 ± 14 vs. 151 ± 11 mm Hg; P < 0.001), but better respiratory mechanics (plateau pressure 27 ± 4 vs. 30 ± 3 cm H(2)O; P = 0.017). Both models led to acute severe pulmonary hypertension. In both models, ECMO (3.7 ± 0.5 L/min), compared with ECCO(2)R (0.4 L/min), increased mixed venous oxygen saturation and oxygenation, and improved hemodynamics (cardiac output = 6.0 ± 1.4 vs. 5.2 ± 1.4 L/min; P = 0.003). [Formula: see text]o(2) and [Formula: see text]co(2), irrespective of lung injury model, were lower during ECMO, resulting in lower Pa(CO(2)) and [Formula: see text]e but worse respiratory elastance compared with ECCO(2)R (64 ± 27 vs. 40 ± 8 cm H(2)O/L; P < 0.001). Conclusions: ECMO was associated with better oxygenation, lower [Formula: see text]o(2), and better hemodynamics. ECCO(2)R may offer a potential alternative to ECMO, but there are concerns regarding its effects on hemodynamics and pulmonary hypertension.