To identify the potential impact of novel therapeutic approaches, we studied the early predictive factors of survival at the onset of acute respiratory distress syndrome (ARDS) in a 24-bed medical ICU of an academic tertiary care hospital. Over a 48-mo period, a total of 3,511 adult patients were admitted and 259 mechanically ventilated patients met ARDS criteria, as defined by American-European consensus conference, i.e., bilateral pulmonary infiltrates and PaO2/FIO2 lower than 200 without left atrial hypertension. These patients were randomly included in a developmental sample (177 patients) and a validation sample (82 patients). Demographic variables, hemodynamic and respiratory parameters, underlying diseases, as well as several severity scores (SAPS, SAPS-II, OSF) and Lung Injury Score (LIS) were collected. These variables were compared between survivors and nonsurvivors and entered into a stepwise logistic regression model to evaluate their independent prognostic roles. The overall mortality rate was 65%. SAPS-II, the severity of the underlying medical conditions, the oxygenation index (mean airway pressure x FIO2 x 100/PaO2), the length of mechanical ventilation prior to ARDS, the mechanism of lung injury, cirrhosis, and occurrence of right ventricular dysfunction were independently associated with an elevated risk of death. Model calibration was very good in the developmental and validation samples (p = 0.84 and p = 0.72, respectively), as was model discrimination (area under the ROC curves of 0.95 and 0.92, respectively). Thus, the prognosis of ARDS seems to be related to the triggering risk factor, the severity of the respiratory illness, and the occurrence of a right ventricle dysfunction, after adjustment for a general severity score.