Background. Damage to the intestine culminating in NEC may occur by reduced mesenteric blood flow, bacterial overgrowth, enteral feeding or a combination of these factors. Antenatal steroids, human milk, lower pH formula, enteral IgA and antibiotics have each been reported to lower the incidence of NEC. In this study, the inclusion of EPL in a PT formula led to an apparent reduction in the incidence of NEC but not other diseases in hospitalized PT infants. Methods. In a randomized, double-masked trial, PT infants (725-1375 g birth weight, n=119) were fed either a control formula (CF) or an egg phospholipid-supplemented formula (EPLF) made by replacing some coconut oil in CF with EPL (75% phosphatidylcholine, 20% phosphatidylethanolamine, 5% other PL). PT and T versions of CF and EPLF were fed from -3 mo to 2 mo and 2 mo to 12 mo, respectively (40 wks gestation = 0 mo). EPLF, but not CF, contained ARA (0.4%) and DHA (0.13%, total fatty acids). Infants were assigned to one of three treatments that were balanced for gender in three stratified weight ranges (725-925 g; 926-1150 g; 1151-1375 g): Control (CF from -3 mo to 12 mo, n=41); Late Supplementation (CF from -3 mo to -1 mo; EPLF from -1 mo to 12 mo, n=44); and Early Supplementation (EPLF from -3 mo to 12 mo, n=34). Subjects lost before 4 mo corrected age were replaced to ensure study of at least 30 infants/group through that age. Infants fed CF and EPLF had similar neonatal, perinatal and demographic characteristics. Results. Fifteen of 85 infants (17.6%) fed CF in hospital (Control and Late Supplementation) and 1 of 34 (2.9%) fed EPLF (Early Supplementation) developed NEC stage II or III (p<0.05). Diet had no apparent effect on other diseases including sepsis (CF, 28.2%; EPLF, 26.5%), BPD (CF,23.4%; EPLF, 23.5%), and ROP (CF,40.0; EPLF,38.2%). The incidence of NEC was higher among male than female infants (11/60 vs 5/59, p,<0.05). All 11 males who developed NEC were fed CF (11/43, 25.6%) (p<0.01 vs males fed EPLF). Summary. EPLF appeared to decrease the incidence of NEC but not other common diseases of PT infants. Conclusion. We speculate that EPL or some component of EPL (e.g., ARA, DHA or choline) protected the immature intestine by one of several plausible mechanisms. A prospective randomized trial to test the effect of EPLF on NEC seems warranted, because NEC remains a major cause of morbidity and mortality among PT infants.