Background: Heated humidified high flow nasal cannula (HHHFNC) is an increasingly used tool for non-invasive ventilation (NIV) in neonates and children needing advanced respiratory support.1 In neonates, common indications for HHHFNC therapy include: respiratory distress syndrome (RDS), post extubation from mechanical ventilation; and other causes of respiratory distress. Its use in Nigeria is not widespread. The aim of this study is to assess the indications, clinical characteristics, outcome and determinants of the successful use of HHHFNC for providing primary respiratory support for neonates referred and needing NIV in a Level III NICU in Nigeria. Methods: This was a retrospective study. All neonates in this study were referred to our facility, Med-Vical Medical Centre, Benin City, Edo State, Nigeria and received HHHFNC for primary respiratory support. Results: The highest indication for primary use of HHHFNC for neonates was respiratory distress syndrome (50.0%). The success rate of HHHFNC in this study was high (70.0%). Although not statistically significant, a higher proportion of neonates in the failure group weighed less than 1kg, while in the successful group, a higher proportion was delivered after 28 weeks. All infants who stayed longer than 7days on admission belonged to the successful group, and none failed HHHFNC therapy. This difference was statistically significant (p=0.011). In conclusion, this study revealed that the success rate of HHHFNC therapy as primary respiratory support in neonates with respiratory distress is high (70.0%), thus it can be used confidently in neonates needing NIV. Length of hospital stay was the only significant factor associated with the successful use of HHHFNC as primary respiratory support.