We aimed to test the diagnostic accuracy in predicting continuous positive airway pressure (CPAP) failure in premature infants with respiratory distress syndrome (RDS) by integrating oxygen saturation (SpO2)/fraction of inspired oxygen (FiO2) (SF ratio) with the measurement of peak velocity of the right diaphragmatic excursions (RD-PV), during the inspiration (I-Peak) and expiratory (E-Peak) phases, performed by pulsed-wave Tissue Doppler imaging. This is a prospective, observational pilot study conducted over a 2-year period. Neonates at ≤ 32 weeks gestation supported by early CPAP were eligible. Natural surfactant was delivered via a minimally invasive technique. We performed serial measurements of SF ratio and RD-PV during the early post-natal hours to test the accuracy in predicting surfactant administration as well as invasive ventilation support within 72 h from birth because of the RDS worsening. Of 56 preterm infants enrolled, 34 (61%) failed CPAP support. SF ratio showed a significant inverse relationship with both Silverman-Andersen score at birth (rho = – 0.417; P = .001) and RD-PV [E-Peak] (rho = – 0.361; P = .007). We achieved a high accuracy in predicting CPAP failure (AUC = 95%; 95% CI, 89-100%) by integrating gender, SF ratio, and RD-PV [E-Peak] at the restricted, multivariate analysis.Conclusions: SF ratio and RD-PV, as measured by pulsed-wave Tissue Doppler, may help physicians to improve their confidence in optimizing therapeutic options in preterm infants with RDS.What is Known:• Continuous positive airway pressure is the recommended first-line treatment for respiratory distress syndrome in preterm infants, but failure rates remain unacceptably high.• Choosing the optimal treatment in terms of non-invasive ventilation effectiveness and timeliness of surfactant administration for these patients is often challenging, also due to our inability to identify a worsening respiratory failure.What is New:• The integration of oxygen saturation, as measured by SpO2/FiO2, with right diaphragm peak motion velocities, as measured by pulsed-wave tissue Doppler, allows for high prediction accuracy of non-invasive ventilation support failure in premature infants at risk of respiratory distress syndrome.• These measurements may help physicians in providing optimal supportive therapy for these patients.