Management of COVID-19-related respiratory failure differs from what is necessary for ARDS. Rather than having alveolar edema, COVID-19 patients have pulmonary vascular dysregulation. Gas exchange is severely compromised with little reduction in lung compliance. Ventilatory support for COVID-19 patients requires higher than normal tidal volumes with minimal PEEP and allowance for higher than usual serum CO2 levels. How the unique pathophysiology of respiratory failure should be treated is discussed by John J. Marini, MD, professor of medicine at the University of Minnesota.