Patients with respiratory failure may remain hypoxemic despite treatment with venovenous extracorporeal membrane oxygenation (VV-ECMO). Therapeutic hypothermia is a potential treatment for such hypoxia as it reduces cardiac output (�˙�) and oxygen consumption. We modified a previously published mathematical model of gas exchange to investigate the effects of hypothermia during VV-ECMO. Partial pressures were expressed as measured at 37°C (α-stat). The effect of hypothermia on gas exchange was examined in four clinical scenarios of hypoxemia on VV-ECMO, each with different physiological derangements. All scenarios had arterial partial pressure of oxygen (PaO2) ≤ 46 mm Hg and arterial oxygen saturation of hemoglobin (SaO2) ≤ 81%. Three had high �˙� with low extracorporeal blood flow to �˙� ratio (�˙EC�˙�). The problem in the fourth scenario was recirculation, with normal �˙�. Cooling to 33°C increased SaO2 to > 89% and PaO2 to > 50 mm Hg in all scenarios. Mixed venous oxygen saturation of hemoglobin as % (Sv¯O2) increased to > 70% and mixed venous partial pressure of oxygen in mm Hg (Pv¯O2) increased to > 34 mm Hg in scenarios with low �˙EC�˙�. In the scenario with high recirculation, Sv¯O2 and Pv¯O2 increased, but to < 50% and < 27 mm Hg, respectively. This in silico study predicted cooling to 33°C will improve oxygenation in refractory hypoxemia on VV-ECMO, but the improvement will be less when the problem is recirculation.