The treatment of respiratory distress in neonates ranges from non-invasive continuous positive airway pressure (CPAP) to advanced invasive mechanical ventilation. Monitoring on CPAP is often done by calculating oxygenation after blood gas analysis which is an invasive procedure. Saturation oxygen pressure index (SOPI) is a simple, non-invasive, bedside tool to monitor the severity of respiratory illness in neonates on CPAP. This study was aimed at validation of SOP index against AaDO2 and determine the cut-off values of SOPI for A-aDO2 of 70, 85 and100. This was a prospective observational study on 126 neonates with respiratory distress and treated with CPAP. The correlation between SOPI and A-aDO2 was validated using Bootstrap method. There was a significant positive correlation between SOPI and A-aDO2 with the Spearman correlation coefficient (rho) being 0.815 (p = 0). The mean coefficient of correlation after Bootstrap was 0.827 (p value < 0.0001). SOPI values of 1.52, 1.57 and 1.6 predicted A-aDO2 value of 70, 85 and 100 with a sensitivity of above 80% and specificity above 90%, respectively.Conclusion: SOPI has a significant positive correlation of 82.7% against A-aDO2 and can be a valuable tool to assess respiratory distress in neonates without arterial blood gas. What is Known: • Saturation oxygen pressure index (SOPI) is a non-invasive monitoring tool for neonates on N-CPAP. • SOPI has a good correlation with AaDO2. What is New: • Correlation of SOPI with AaDO2 is now validated. • Values between 1.52 and 1.88 indicate clinically useful range of AaDO2 for escalation of respiratory support from CPAP.