<p>Enteral nutrition with a nasogastric/orogastric feeding tube is essential in premature infants. These feeding tubes are placed either by clinical teams in the hospital setting or by parents at home. These tubes can be placed incorrectly or may dislodge after placement. Existing methods for confirming placement such as auscultation, testing gastric aspirates, and radiography have limitations, necessitating alternative solutions to improve safety and accuracy of placement. Here, we describe the clinical feasibility of a novel feeding tube with impedance and temperature sensors. The information received from the sensors is integrated to decipher real-time position, specifically using an airway misplacement algorithm (AMA) and gastric placement algorithm (GPA). We tested the feasibility and validity of this approach in a two-part clinical study involving premature neonates. In the Phase 1 study (<i>n</i> = 16), feeding tubes were placed without any real-time guidance; data from this study was then used to develop the algorithms that provided real-time guidance for placements in the Phase 2 study (<i>n</i> = 10). Results showed AMA and GPA detected placement (or misplacement) 100% of the time, demonstrating clinical feasibility and safety of impedance and temperature integrated feeding tubes for real-time placement guidance.</p>