Background: High-frequency oscillatory ventilation (HFOV) has been shown to result in less lung injury. HFOV is also used in critically ill newborns when conventional mechanical ventilation (CV) fails, especially in units with lack of nitric oxide (NO) and extracorporeal membrane oxygenation. Objectives: There are no recent data on the response of newborns to rescue HFOV (rHFOV) in the literature. The aim of this study was to evaluate the risk factors that affect the response to rHFOV in newborns who had CV failure in respiratory support. Methods: Newborns who still had a respiratory failure in case of CV and switched to rHFOV were grouped as survived and died. The characteristics of the patients such as birth weight (BW), gestational age (GA), and disease, in addition to ventilator settings, arterial blood gas analysis, ventilation duration, and side effects were compared between the groups. Results: 84 patients with a mean GA of 32. 1 5. 3 weeks and a mean BW of 1901 1135 g were enrolled in the study. The patients were switched to rHFOV at median 28. 5 hours of life. Infants who died had lower BW (1345 935 g vs. 2557 1035 g, P = 0. 0001) and lower GA (31. 7 4. 9 weeks vs. 34. 8 4. 4 weeks, P = 0. 03) in comparison with infants who survived. Prematurity (OR: 7. 73, 95% CI: 2. 1-24. 7, P = 0. 001) and having BW < 1500 g (OR: 7. 02, 95% CI: 2. 6-18. 6, P < 0. 001) increased mortality significantly. Cut-off values for BW and GA were found to be 1875 g and 32. 5 weeks with 75% sensitivity and 78% specificity. There were no differences in the initial ventilation settings between the groups and no correlation between the side effects such as intraventricular hemorrhage, retinopathy of prematurity, and bronchopulmonary dysplasia could be demonstrated with the duration of rHFOV. Conclusions: rHFOV in case of CV failure is more effective in patients with greater GA andBW, independent of the disease and initial rescue ventilator settings.