OBJECTIVES:: Necrotizing enterocolitis (NEC) is complex disease thought to occur due to an immaturity of gastrointestinal tract of preterm infants. Intestinal dysfunction induced by total parental nutrition (TPN) may increase the risk for NEC upon introduction of enteral feeding. We hypothesized that the intestinal trophic and anti-inflammatory actions previously ascribed to the gut hormone, GLP-2, would reduce the incidence of NEC when given in combination with TPN in preterm piglets. METHODS:: Preterm, newborn piglets were nourished by TPN and infused continuously with either human GLP-2 (100 μg·kg·d) or control saline for 2 days (n = 12/grp). On day 3, TPN was discontinued and pigs were given orogastric formula feeding every 3 hr and continued GLP-2 or control treatment until the onset of clinical signs of NEC for an additional 96 hours and tissue was collected for molecular and histological endpoints. RESULTS:: GLP-2 treatment delayed the onset of NEC but was unable to prevent a high NEC incidence (∼70%) and severity that occurred in both groups. GLP-2-treated pigs had less histological injury and increased proximal intestinal weight and mucosal villus height, but not crypt depth or Ki-67 positive cells. Inflammatory markers of intestinal myeloperoxidase were unchanged and serum amyloid A levels were higher in GLP-2-treated pigs. CONCLUSION:: GLP-2 did not prevent NEC and a proinflammatory response despite some reduction in mucosal injury and increased trophic effect.