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Background: To evaluate the severity of respiratory failure among newborns with respiratory distress syndrome (RDS), oxygenation index (OI) has been implemented. In the present study, we assessed the accuracy of oxygen saturation index (OSI) in determining the severity of respiratory failure.Methods: A cross-sectional study was carried out in the NICUs of two Iranian Hospitals (Tehran, Iran) in 2018. Preterm neonates with RDS entered the study. Immediately after admission, the severity of RDS was determined based on RDS scoring system. Then, 2 CC of arterial blood was withdrawn and sent to laboratory determining blood gases. Simultaneously, the level of peripheral capillary oxygen saturation (SpO2) was read using pulse oximeter and recorded. OI and OSI were measured using the formulae. Receiver Operating Characteristic curve, Kappa agreement coefficient and accuracy, sensitivity and specificity was used to compare the OI and OSI results.Results: In the study, 95 neonates were considered. Based on ROC curves, the appropriate cut off with AUC = 0.99 for severe respiratory failure was OSI >8. The sensitivity, specificity, negative predicted value, and positive predicted value for the OSI Cut off >8 were 100, 98, 0.97 and 100%, respectively. The overall accuracy and Kappa agreement between OSI and OI was 0.96 and 0.98%, respectively.Conclusion: Our results showed that OSI with high sensitivity, specificity values could predict the severity of respiratory failure in preterm neonates with RDS. [ABSTRACT FROM AUTHOR]