In a recent short-term physiological study, we demonstrated a new continuous positive airway pressure (CPAP) system (neonatal helmet-CPAP) that could be a feasible device for managing preterm infants needing continuous distending pressure with better tolerability than nasal-CPAP. However, its application for a long-term period has never been reported in neonates. Here, we describe the use of neonatal helmet-CPAP in a neonate with persistent pulmonary hypertension of the newborn. Twenty minutes after neonatal helmet-CPAP placement, the baseline post-ductal tcSaO2 (66%) and alveolar-arterial gradient O2 improved from 66% and 648 mmHg to 100% and 465 mmHg, respectively. The neonatal helmet-CPAP was applied for 48 hours and was well-tolerated by the patient without complications. Long-term use of neonatal helmet-CPAP appears feasible and well-tolerated. Comparative trials are needed.