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Traditional measures of ARDS severity such as Pao2/Fio2 may not reliably predict clinical outcomes. The oxygenation index (OI [Fio2 × mean airway pressure × 100)/Pao2]) may more accurately reflect ARDS severity but requires arterial blood gas measurement. We hypothesized that the oxygenation saturation index (OSI [Fio2 × mean airway pressure × 100)/oxygen saturation by pulse oximetry (Spo2)]) is a reliable noninvasive surrogate for the OI that is associated with hospital mortality and ventilator-free days (VFDs) in patients with ARDS.Critically ill patients enrolled in a prospective cohort study were eligible if they developed ARDS (Berlin criteria) during the first 4 ICU days and had mean airway pressure, Spo2/Fio2, and Pao2/Fio2 values recorded on the first day of ARDS (N = 329). The highest mean airway pressure and lowest Spo2/Fio2 and Pao2/Fio2 values were used to calculate OI and OSI. The association between OI or OSI and hospital mortality or VFD was analyzed by using logistic regression and linear regression, respectively. The area under the receiver-operating characteristic curve (AUC) for mortality was compared among OI, OSI, Spo2/Fio2, Pao2/Fio2, and Acute Physiology and Chronic Health Evaluation II scores.OI and OSI were strongly correlated (rho = 0.862; P < .001). OSI was independently associated with hospital mortality (OR per 5-point increase in OSI, 1.228 [95% CI, 1.056–1.429]; P = .008). OI and OSI were each associated with a reduction in VFD (OI, P = .023; OSI, P = .005). The AUC for mortality prediction was greatest for Acute Physiology and Chronic Health Evaluation II scores (AUC, 0.695; P < .005) and OSI (AUC, 0.602; P = .007). The AUC for OSI was substantially better in patients aged < 40 years (AUC, 0.779; P < .001).In patients with ARDS, the OSI was correlated with the OI. The OSI on the day of ARDS diagnosis was significantly associated with increased mortality and fewer VFDs. The findings suggest that OSI is a reliable surrogate for OI that can noninvasively provide prognostic information and assessment of ARDS severity.