OBJECTIVES: High flow therapy (HFT) has been demonstrated to be a safe and effective noninvasive respiratory support technique for the treatment of pre-term infants in neonatal intensive care units (NICU). Our objective was to develop a quantitative framework based on available evidence to estimate the economic impact of adoption of a HFT respiratory support strategy compared to current standard of care. METHODS: We constructed a model to estimate total cost per NICU episode of care by treatment strategy, considering utilization and duration of the different types of ventilatory support modalities – conventional mechanical ventilation (CMV), nasal continuous positive airway pressure (nCPAP) ventilation, and HFT – as well as utilization levels of surfactant, chest x-rays, blood gas analyses and total NICU length of stay. Model parameters were derived from a recent study comparing respiratory modality utilization between five US-based neonatal intensive care units (NICUs) adopting a HFT strategy and a larger pool of NICUs in the Vermont-Oxford Network (VON), and from single center experience. We computed the total cost difference between the respiratory support strategies based on published cost data. Parameter uncertainty was tested in sensitivity analyses. RESULTS: The base case analysis resulted in total average length of ventilation of 25.48 days for the non-HFT strategy (8.92 days nCPAP, 6.10 days HFT, 10.47 days CMV) and of 25.06 days (2.88 days nCPAP, 16.86 days HFT, 5.32 days CMV) for the HFT strategy. HFT was associated with total projected cost savings of $2,317. Results were sensitive to length of HFT use, length of CMV, cost of HFT, and length of nCPAP support. CONCLUSIONS: Adoption of a HFT strategy appears to be associated with meaningful savings in total NICU episode of care costs, primarily resulting from reductions in the time of conventional mechanical ventilation. Further research is warranted to substantiate these findings.