Objective: To examine the ontogeny of salivary epidermal growth factor (sEGF) in premature infants and to determine the relation of sEGF to the development of necrotizing enterocolitis (NEC). Study design: Salivary EGF was prospectively measured in 327 infants with gestational ages from 23 weeks to term. Infants of ≤32 weeks' gestation (n = 261) were followed with weekly sEGF measurements through 3 weeks of life. Multivariable regression analyses were used to determine variables significantly related to sEGF levels and to identify predictors of NEC. Results: Over the first 3 weeks of life, sEGF increased across gestational age and postnatal age categories. In multivariable models, gestational age was a significant predictor of sEGF levels (P < .009). In a cohort of 27 infants who had NEC, gestational age, race, and changes in sEGF levels between weeks of life 1 and 2 were predictive of the development of NEC. These infants had lower sEGF at week 1 and greater increases from week 1 to week 2 compared with infants without NEC. Conclusions: There is a positive relation between sEGF levels and gestational age. Patterns of sEGF levels over the first 2 weeks of life were significantly related to development of NEC in very low birth weight infants.