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Background: Early recognition of high-risk-patients with acute respiratory distress syndrome (ARDS) might improve their outcome by less protracted allocation to intensified therapy including extracorporeal membrane oxygenation (ECMO). Among numerous predictors and classifications, the American European Consensus Conferenece (AECC)- and Berlin-definitions as well as the oxygenation index (OI) and the Murray-/Lung Injury Score are the most common. Most studies compared the prediction of mortality by these parameters on the day of intubation and/or diagnosis of ARDS. However, only few studies investigated prediction over time, in particular for more than three days., Objective: Therefore, our study aimed at characterization of the best predictor and the best day(s) to predict 28-days-mortality within four days after intubation of patients with ARDS., Methods: In 100 consecutive patients with ARDS severity according to OI (mean airway pressure*FiO2/paO2), modified Murray-score without radiological points (Murray_mod), AECC- and Berlin-definition, were daily documented for four days after intubation. In the subgroup of 49 patients with transpulmonary thermodilution (TPTD) monitoring (PiCCO), extravascular lung water index (EVLWI) was measured daily., Primary Endpoint: Prediction of 28-days-mortality (Area under the receiver-operating-characteristic curve (ROC-AUC)); IBM SPSS 26., Results: In the totality of patients the best prediction of 28-days-mortality was found on day-1 and day-2 (mean ROC-AUCs for all predictors/scores: 0.632 and 0.620). OI was the best predictor among the ARDS-scores (AUC=0.689 on day-1; 4-day-mean AUC = 0.625). AECC and Murray_mod had 4-day-means AUCs below 0.6. Among the 49 patients with TPTD, EVLWI (4-day-mean AUC=0.696) and OI (4-day-mean AUC=0.695) were the best predictors. AUCs were 0.789 for OI on day-1, and 0.786 for EVLWI on day-2. In binary regression analysis of patients with TPTD, EVLWI (B=-0.105; Wald=7.294; p=0.007) and OI (B=0.124; Wald=7.435; p=0.006) were independently associated with 28-days-mortality. Combining of EVLWI and OI provided ROC-AUCs of 0.801 (day-1) and 0.824 (day-2). Among the totality of patients, the use of TPTD-monitoring "per se" and a lower SOFA-score were independently associated with a lower 28-days-mortality., Conclusions: Prognosis of ARDS-patients can be estblished within two days after intubation. The best predictors were EVLWI and OI and their combination. TPTD-monitoring "per se" was independently associated with reduced mortality., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Wolfgang Huber is member of the Medical Advisory Board of Pulsion Medical Systems SE, Feldkirchen, Germany. All other authors have no conflict of interest. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.