Background: High-frequency oscillatory ventilation (HFOV) presents challenges for non-invasive CO 2 monitoring due to its rapid oscillations. This study examines the feasibility of instantaneous CO 2 partial pressure (INST CO 2) monitoring during HFOV with a capnometer equipped with a mainstream CO 2 sensor. Methods: This study included seven neonates receiving HFOV in the neonatal intensive care unit (NICU) at Shizuoka Children’s Hospital. INST CO 2 values were recorded over 3- and 5-min intervals surrounding each blood gas sampling to determine the maximum INST CO 2 value (INST CO 2 MX). The primary outcome was the correlation between INST CO 2 MX and arterial partial pressure of carbon dioxide (PCO 2). Results: A total of 216 paired INST CO 2 MX and PCO 2 values were analyzed. The coefficient of determination ( R 2) was 0.571 for INST CO 2 MX (3 min) and 0.579 for INST CO 2 MX (5 min). Univariable and multivariable analyses revealed that a lower fraction of inspired oxygen (FiO 2), reduced minute ventilation, and increased postnatal age were associated with improved concordance between INST CO 2 MX and PCO 2. Conclusion: INST CO 2 MX demonstrated a strong correlation with PCO 2 in neonates undergoing HFOV. This novel, non-invasive monitoring approach may serve as a valuable tool for neonatal respiratory management. Future research is needed to validate these findings in broader patient populations and across various ventilatory settings.