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Objectives: We hypothesize that elevated soluble suppression of tumorigenicity-2 concentrations, a marker of pulmonary epithelial injury, reflect ongoing lung injury in acute hypoxemic respiratory failure due to coronavirus disease 2019 and associate with continued ventilator dependence., Design: We associated serial plasma soluble suppression of tumorigenicity-2 levels and markers of systemic inflammation including d-dimer, C-reactive protein, and erythrocyte sedimentation rate with 30-day mortality and ventilator dependence., Setting: Adult medical ICUs and general medicine wards at an academic teaching hospital in Boston, MA., Patients: Adult patients with severe acute respiratory syndrome coronavirus 2 infection and acute hypoxemic respiratory failure admitted to the ICU ( n = 72) and non-ICU patients managed with supplemental oxygen ( n = 77)., Interventions: Observational study from April 25 to June 25, 2020., Measurements and Main Results: ICU patients had a higher baseline body mass index and median soluble suppression of tumorigenicity-2, d-dimer, and C-reactive protein concentrations compared with non-ICU patients. Among ICU patients, elevated baseline modified Sequential Organ Failure Assessment score and log (soluble suppression of tumorigenicity-2) were associated with 30-day mortality, whereas initial Pao 2 /Fio 2 and markers of systemic inflammation were similar between groups. Only log (soluble suppression of tumorigenicity-2) associated with ventilator dependence over time, with the last measured log (soluble suppression of tumorigenicity-2) concentration obtained on ICU day 11.5 (interquartile range [7-17]) higher in patients who required reintubation or tracheostomy placement compared with patients who were successfully extubated (2.10 [1.89-2.26] vs 1.87 ng/mL [1.72-2.13 ng/mL]; p = 0.03). Last measured systemic inflammatory markers, modified Sequential Organ Failure Assessment score, and Pao 2 /Fio 2 were not different between patients who were successfully extubated compared with those with continued ventilator dependence., Conclusions: Plasma soluble suppression of tumorigenicity-2 is a biomarker readily measured in blood that can provide dynamic information about the degree of a patient's lung injury and real-time assessment of the likelihood of extubation success. Measures of systemic inflammation, illness severity, and oxygenation did not associate with ventilator outcomes., Competing Interests: Dr. Januzzi is a Trustee of the American College of Cardiology, has received grant support from Novartis Pharmaceuticals, HeartFlow Inc, Innolife, Applied Therapeutics and Abbott Diagnostics, consulting income from Abbott, Janssen, Novartis, Pfizer, Merck, and Roche Diagnostics, and participates in clinical endpoint committees and data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, and Takeda. Dr. Thompson reports receiving consulting fees from Bayer, Novartis, and Thetis, outside the submitted work; he receives institutional grants from the NHLBI. Dr. Medoff reports sponsored research agreements with Bristol Myers Squibb, Boehringer Ingelheim, Sanofi, and Bayer and serves on advisory boards for Sanofi and Regeneron. The remaining authors have not disclosed any potential conflicts of interest., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)