Nasal continuous positive airway pressure (NCPAP) is an accepted form of non-invasive ventilation in preterm infants. Few, if any, studies have shown an advantage of one type of NCPAP over another. It has been theorized that bubble-generated NCPAP may be advantageous for the preterm neonate versus traditionally used ventilator-generated NCPAP. The aim of this study was to examine for any short-term differences in physiologic parameters in preterm subjects receiving these two different methods of NCPAP. We conducted a randomized, prospective, cross-over pilot study of preterm infants being treated with NCPAP in the neonatal intensive care unit. Subjects were continuously monitored for several physiologic parameters including heart rate, respiratory rate, oxygen saturation, cerebral tissue oxygen saturation and cerebral fractional oxygen extraction using routine neonatal monitors and near-infrared spectroscopy (NIRS) while on 2 h of bubble NCPAP and 2 h of ventilator NCPAP. Subjects were randomized to be monitored while either starting on bubble NCPAP and then switching to ventilator NCPAP or starting on ventilator NCPAP and switching to bubble NCPAP. Eighteen subjects were included. We found no statistically significant difference in any of the physiologic parameters while subjects were receiving bubble NCPAP versus ventilator NCPAP during the monitoring time periods. While on bubble NCPAP, subjects showed a trend toward decreasing respiratory rate and decreasing cerebral fractional oxygen extraction over time, but this did not reach statistical significance. There appears to be no difference in immediate physiologic effects between bubble NCPAP and ventilator NCPAP. This does not preclude the possibility of potential long-term differences, but any differences seen would likely be based on mechanisms that take more time to develop. A larger prospective trial is warranted to confirm our findings.