Necrotizing enterocolitis (NEC) develops primarily after the onset of enteral feeds in the premature infant. The purpose of this study was to evaluate the influence of intestinal luminal nutrients on histologic injury and the oxidant response in a rat model of NEC. On postnatal Days 10 and 35, Sprague-Dawley rats (total n = 81) underwent abdominal laparotomy. A control group received sham-injury only. The ischemia groups received a single intraluminal injection of 0.25 ml (Day 10) or 1.0 ml (Day 35) of lactose (8.6 g/dl), casein (2.2 g/dl), corn oil (4.4 g/dl), or infant formula (Similac; 20 g/dl). After injection of the nutrient solutions, ischemia groups underwent mesenteric occlusion for 1 hr and intraluminal injection of platelet-activating factor (50 microgram/kg). Necropsies were performed after 6 hr or at demise. Intestinal samples were taken for histology, total glutathione (GSH; an antioxidant), and conjugated dienes (a lipid peroxidation product). Histologic injury was scored from 0 (normal) to 5 (transmural necrosis). Microscopic injury scores in the oil group were significantly higher than the casein group (P < 0.05) and trended toward being higher in the formula group (P = 0.085) at age 10 days. Total GSH activity was significantly higher in the sham groups than all ischemia groups on Day 10 (P < 0.001) and than the corn oil group on Day 35 (P < 0.05). GSH activity did not differ among ischemia groups. Conjugated diene concentrations were significantly higher in the casein group than the lactose and sham groups at age 10 days (P < 0.05) only. We conclude that intraluminal lipids may augment intestinal ischemic injury in the newborn (age 10 days) but not the weanling rat. While oxygen-free radicals were present during injury, lipid peroxidation from oxygen radicals was not responsible for this increase in histologic injury.