<b><i>Background:</i></b> Noninvasive ventilation has been used increasingly in recent years to minimize the duration of endotracheal mechanical ventilation in neonates due to its association with lung injury. Nasal high-frequency oscillation (nHFO) is a relatively new noninvasive modality but evidence for its use is limited. <b><i>Objective:</i></b> The goal of this study was to compare the CO<sub>2</sub> clearance efficacy of nHFO and noninvasive positive pressure ventilation (NIPPV) in a neonatal lung model. <b><i>Design/Methods:</i></b> A newborn mannequin with dimensions and anatomy similar to a term infant was utilized. It was connected to a commercially available neonatal mechanical ventilator using a manufacturer-provided nasal adaptor. Various modes of noninvasive ventilation were compared as CO<sub>2</sub> clearance was measured at the oropharynx by an end-tidal CO<sub>2</sub> analyzer following the addition of a known amount of CO<sub>2</sub> into the lung. Measurements were obtained at two different lung compliances using nHFO and compared with nCMV and nasal continuous positive airway pressure (nCPAP) as a control. Pressures near the nasal adaptor and the larynx were simultaneously measured with in-line pressure transducers. <b><i>Results:</i></b> Whereas no CO<sub>2</sub> elimination was observed under nCPAP, its clearance with nHFO was 3-fold greater as compared to NIPPV. On nHFO, CO<sub>2</sub> clearance was inversely proportional to frequency and maximal at 6 and 8 Hz. At a lower lung compliance, CO<sub>2</sub> clearance was significantly higher at 6 Hz as compared to 10 Hz. During nHFO set to deliver a MAP of 10.0, we documented pressures of 7.2 ± 0.3 at the nasal adaptor and only 2.3 ± 0.3 cm H<sub>2</sub>O at the larynx. <b><i>Conclusions:</i></b> Nasal HFO is effective and superior to NIPPV at lung CO<sub>2</sub> elimination in a newborn mannequin model. The use of nHFO as the preferred mode of noninvasive ventilation warrants further clinical studies.