Background and Objectives Respiratory distress syndrome (RDS) and ventilation‐induced lung injury lead to significant morbidity in preterm infants. High‐frequency oscillatory ventilation with volume‐guarantee (HFOV‐VG) has been used as a rescue therapy and might lead to lower rates of death and bronchopulmonary dysplasia, especially when using low tidal volumes and high frequencies. The aim of the study was to define HFOV‐VG parameters leading to adequate ventilation in the first 72 h of preterm RDS using a low volume and high‐frequency strategy. Design and Methods Retrospective cohort study in a tertiary‐level neonatology unit. Infants <32 weeks with severe respiratory insufficiency needing HFOV‐VG were included. Patients were ventilated following a standard mechanical ventilation aiming for low tidal volumes and high frequencies. Clinical data, perinatal characteristics and high‐frequency parameters corresponding with adequate ventilation were recorded. Results 116 patients were included. Median gestational age was 25 weeks (interquartile range IQR = 24–27), median birth weight 724 g (IQR = 600–900 g). HFOV‐VG was started at 2 h, median high‐frequency tidal volume was 1.63 ml/kg (IQR = 1.44–1.84) and median frequency was 16 Hz (IQR = 15–18). Weight‐adjusted tidal volumes did not depend on gestational age, antenatal corticosteroids nor chorioamnionitis, and were inversely correlated with frequencies (R 2 = −0.10, p = .001). Conclusion HFOV‐VG can reach adequate ventilation at high frequencies when using adequate volumes, providing a feasible ventilation strategy that might be of help in preterm infants with RDS.