Abstract. Objective: Simultaneous monitoring of cerebral and mesenteric tissue saturations were recorded in preterm neonates using near infrared spectroscopy (NIRS) to evaluate if NIRS method can be improved to compensate for the optical absorption properties of stool interference, particularly meconium and transitional stools, in order to reliably measure gastrointestinal (GI) tissue oxygen saturation. Study design: With parental agreement, we used a 4-wavelength cerebral & tissue oximeter (FORE-SIGHT®, CAS Medical Systems, Branford, CT USA) to monitor premature neonates. The NIRS sensors were placed in the right lower quadrant of the abdomen and the forehead, with continuous data collection every 2 seconds for 72 hours. Simultaneously, continuous peripheral pulse oximetry (SpO2) was recorded. Feeding regimens, stooling patterns and clinical outcomes were recorded. Raw data from FORE-SIGHT were recorded and analyzed using a prototype neonatal stool compensation algorithm. Results: Twenty-three preterm neonates with adjusted gestational ages of 26–34 weeks, weighing 740–1930 grams were studied. NIRS stool interference level was determined for all subjects, and found to be extremely variable. High and Very High stool interference occurred for subjects passing meconium. Moderate and High stool interference resulted in erroneously computed very low GI StO2 using traditional NIRS methods. Stool compensated GI StO2 measurements showed a higher correlation to cerebral SctO2 and pulse oximetry SpO2 in subjects with healthy bowel. Conclusion: Measurement of mesenteric saturations via NIRS proves to be a useful tool in neonates. A NIRS algorithm that compensates for interference caused by meconium and transitional stools shows promising results to measure GI StO2 accurately.