Venovenous extracorporeal membrane oxygenation (VV-ECMO) has been used during the COVID-19 pandemic to support patients with the most severe cases of COVID-19 acute respiratory distress syndrome (ARDS). The earliest investigations of VV-ECMO use in COVID-19 ARDS reported outcomes similar to prepandemic ARDS cohorts, with mortality <40%.¹ However, studies conducted during subsequent waves of the pandemic painted a worse picture, with mortality between 50% to 73%.^2,3 Although variant-specific pathology and increased severity of disease have been suggested as culprits, other potential contributors include higher incidences of delirium, right ventricular (RV) failure, and persistent hypoxemia while on VV-ECMO than previously encountered.^4,5 Persistent hypoxemia is particularly problematic, as routine measurements of oxygenation frequently are misunderstood and may lead to inappropriate treatment changes and complications. In fact, many centers around the country now set oxygenation goals incongruent with Extracorporeal Life Support Organization (ELSO) guidelines. Therefore, it is important to revisit the physiology of VV-ECMO oxygenation, clarify the clinical relevance of apparent persistent hypoxemia in this patient population, and illustrate how its misunderstanding may lead to initiation of therapies associated with harm.