Nasal continuous positive airway pressure (CPAP) is reportedly superior to mechanical ventilation in the neonatal population by reducing bronchopulmonary dysplasia (BPD). The neonate is vulnerable to injury secondary to immature physiological systems and skin structures and the current CPAP devices place constant pressure on nares, nasal septum and forehead, increasing injury risk. Through the framework of comparative effectiveness research an examination of nasal interfaces currently used during neonatal CPAP was conducted in an effort to provide scientifically supported recommendations and improve clinical outcomes. The primary aim of this study was to determine differences in the frequency, severity and specific types of nasal injuries described when comparing different nasal CPAP interfaces (prongs/mask/rotation) used in the treatment of neonatal respiratory distress syndrome (RDS). A secondary aim of the study was to identify risk factors that may be associated with skin breakdown during nasal CPAP administration. A three group prospective randomized experimental design was used to study78 neonates <1500 grams receiving nasal CPAP using the same delivery system. The subjects were randomized into three groups: 1) continuous nasal prong group, 2) continuous nasal mask group, or 3) alternating mask/prongs group. Serial data collection included: demographic, biophysical measures and the Neonatal Skin Condition Scale (NSCS). This study demonstrated a significant difference in the frequency and severity of skin injury when utilizing a method of rotating mask and prong nasal interfaces during neonatal CPAP therapy; a useful clinical recommendation. Specific nursing care implications related to study findings include; choosing a device for best fit for infant (face shape and infant size); positioning of the CPAP device; developmental position of the infant; and focused skin assessment with rapid intervention. Standardized care including skin barriers, clinical expertise of nursing and respiratory therapy, and skin care management are strategies that warrant additional research.