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The Sequential Organ Failure Assessment (SOFA) score is validated to measure severity of organ dysfunction in critically ill patients. However, in some practice settings, daily arterial blood gas data required to calculate the respiratory component of the SOFA score are often unavailable. The objectives of this study were to derive Spo2/Fio2 (SF) ratio correlations with the Pao2/Fio2 (PF) ratio to calculate the respiratory parameter of the SOFA score, and to validate the respiratory SOFA obtained using SF ratios against clinical outcomes.We obtained matched measurements of Spo2 and Pao2 from two populations: group 1—patients undergoing general anesthesia and group 2—patients from the acute respiratory distress syndrome network—low-vs. high-tidal volume for the acute respiratory management of acute respiratory distress syndrome database. Using a linear regression model, we first determined SF ratios corresponding to PF ratios of 100, 200, 300, and 400. Second, we evaluated the contribution of positive end-expiratory pressure (PEEP) on the relationship between SF and PF, for patients on PEEP in centimeters of water (cm H2O) of <8, 8-12, and >12. Third, we calculated the SOFA scores in a separate cohort of intensive care unit patients using the derived SF ratios and validated them against clinical outcomes.The total SOFA scores calculated using SF ratios and PF ratios were highly correlated (Spearman’s rho 0.85, p < 0.001) in all patients and in the three stratified PEEP categories (<8 cm H2O, Spearman’s rho 0.87, p < 0.001; PEEP 8-12 cm H20, Spearman’s rho 0.85, p < 0.001; PEEP >12 cm H2O, Spearman’s rho 0.85, p < 0.001). The respiratory SOFA scores based on SF ratios and PF ratios correlated similarly with intensive care unit length of stay and ventilator-free days, when validated in a cohort of critically ill patients.The total and respiratory SOFA scores obtained with imputed SF values correlate with the corresponding SOFA score using PF ratios. Both the derived and original respiratory SOFA scores similarly predict outcomes.