Abstract. OBJECTIVE: our objective is to assess the positive distending pressure generated by high flow nasal cannula and nasal continuous positive airway pressure by measuring the end esophageal pressure in premature infants. STUDY DESIGN: This is a pilot, non-randomized, open label, uncontrolled, crossover assignment study that included neonates born with a birth weight of 1750 grams or less and receiving nCPAP ventilatory support for 24 hrs or more and requiring FiO2 21–50% on nCPAP. Each infant was started on nCPAP at 4, 6 and 8 cm H2O then on three levels of HHHFNC, 4 L/min, 6 L/min and 8 L/min with 4 hours interval on each flow level. Esophageal pressure (EP), apnea of prematurity, FiO2 requirements and bradycardia were recorded during the different levels of CPAP and HHHFNC use. RESULTS: The study showed that there were no complications observed during the study such as pneumothorax. It showed that EP created by the three different levels of HHHFNC were slightly higher than that EPs created by the three different levels of nCPAP, but statistically not significant. There was no significant change in the FiO2 requirements during the study. There was a trend towards the improvement of oxygen saturation in HHHFNC at different levels and it was statistically significant when 8 L/min was used (P 0.0214). The rates of bradycardia and apnea in nCPAP and HHHFNC were low and statistically were not significant, however the episodes of bradycardia were less in HHHFNC and they were statistically significant at the level of 6 L/min. CONCLUSIONS: HHHFNC in premature infants was well-tolerated with no adverse side effects such as pneumothorax, desaturation, apnea and bradycardia. The study also showed that HHHFNC was able to deliver distending pressure equal to nCPAP. Moreover, we have observed a significant improvement in oxygen saturation when higher levels of HHHFNC was used, most probably due to the improvement of infant comfort which is a noticeable feature of HHHFNC.