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Background: We aimed to evaluate the predictive value of the end-tidal CO2 (EtCO2) alone or combined with ventilation related parameters on Spontaneous Breathing Trial (SBT) outcome on mechanically ventilated patients., Methods: Prospective observational study in a medical Intensive Care Unit. Mechanically ventilated adult patients who met predefined criteria for weaning were included. Patients underwent a T-piece SBT for 30 minutes and the hemodynamic and respiratory clinical parameters including EtCO2 were recorded every five minutes., Results: The study included 280 patients, who were studied (age: 64±17 years, SAPS II: 44 [34-56]) during a first SBT and 76 patients during a second SBT. The Weaning Index, defined as the product of the respiratory rate and EtCO2, was a strong early predictive factor of SBT outcome; at 10 minutes, the area under the curve (AUC) was 86% ([80-90], P<0.0001) during the first SBT and 88% ([80-96], P<0.0001) during the second SBT. After 10 minutes of SBT, a Weaning Index >1100 identified patients that will not successfully complete the SBT at 30 minutes with a specificity of 98%., Conclusions: In unselected mechanically ventilated patients, the Weaning Index is helpful to early identify patients who will fail the SBT during a first and a second trial.