OBJECTIVES: High-frequency oscillatory ventilation with volume guarantee (HFOV with VG) can optimize respiratory support in preterm infants. However, its superiority over conventional HFOV remains uncertain. This systematic review aimed to analyze ventilatory and clinical effects of HFOV with VG compared with conventional HFOV in neonates under 44 weeks corrected gestational age. METHODS: We systematically searched Pubmed, EMBASE, Cochrane, and ClinicalTrials.gov from inception until August 4th, 2023, to identify randomized or observational studies comparing HFOV with VG with HFOV without VG in in neonates under 44 weeks corrected gestational age. Outcomes of interest included high-frequency tidal volume (VThf) and amplitude oscillations, carbon dioxide diffusion coefficient (DCO2) and carbon dioxide partial pressure (PaCO2) mean values, and episodes of hypocarbia or hypercarbia, hypoxemia episodes, duration of mechanical ventilation, rates of bronchopulmonary dysplasia and intraventricular hemorrhage, and death. ROB-2 and ROBINS were used for risk of bias assessment. RESULTS: This study included 260 patients from two crossover and four cohort studies. Gestational age at birth ranged from 23 to 29 weeks. The included studies presented a considerable risk of bias. A meta-analysis could not be performed, due to the differences in studies’ design, relevant risk of bias, incomplete reporting, and differences in ventilatory settings and reference values adopted. Report of the findings suggest that HFOV with VG, compared with HFOV, may reduce VThf variability and, consequently, hypo- and hypercarbia episodes. However, no significant differences in terms of BPD, IVH or mortality were observed. CONCLUSION: This systematic review does not provide evidence of the superiority of HFOV with VG over conventional HFOV in the context of ventilation of preterm infants, indicating the need for further studies evaluating the effects of VG on HFOV.