Background Recent evidence suggests that antecedent red blood cell (RBC) transfusions increase the risk for necrotizing enterocolitis (NEC), the most common gastrointestinal emergency encountered by very-low-birthweight (VLBW) infants. The underlying mechanism for this association is unknown. Altered oxygenation of the mesenteric vasculature during RBC transfusion has been hypothesized to contribute to NEC development and was investigated in this study. Study Design and Methods Oxygenation patterns among four VLBW infants who developed transfusion-related NEC (TR-NEC) were compared to four VLBW infants with similar gestational age who were transfused but did not develop NEC (non-NEC). Cerebral and mesenteric patterns were recorded before, during, and 48 hours after RBC transfusion using near-infrared spectroscopy (NIRS) technology. Percentage change from mean baseline regional oxygen saturation values and cerebrosplanchnic oxygenation ratios were analyzed. Results All TR-NEC infants (24-29 weeks' gestation; 705-1080 g) demonstrated greater variation in mesenteric oxygenation patterns surrounding transfusions than non-NEC infants (27.6-30 weeks' gestation; 980-1210 g). TR-NEC infants received larger mean volumes of total blood (27.75 ± 8.77 mL/kg) than non-NEC infants (15.25 ± 0.5 mL/kg). Conclusion Wide fluctuation and decreases in mesenteric oxygenation patterns are more pronounced in TR-NEC infants, especially before TR-NEC onset, compared to non-NEC infants. Greater total volume of infused blood was associated with TR-NEC in preterm infants. Using NIRS, larger prospective studies are needed to further evaluate potential risk factors for NEC in this high-risk population.