To investigate factors associated with risk and age of onset for necrotizing enterocolitis (NEC), a retrospective case-control review was performed of patients with NEC and control infants matched for birthweight and date of admission. NEC cases were defined by Bell staging criteria and were included if pneumatosis intestinalis, histologic confirmation, or a recognized complication of NEC was identified in association with clinical signs and symptoms. NEC was significantly related to birthweight and premature post-conceptional age. In contrast to control infants, patients with NEC had higher 5 minute Apgar scores, less significant respiratory disease, and more rapid feeding practices. Two distinct subgroups of patients with NEC based on postnatal age of onset were apparent. Patients with early onset NEC (21 days or less postnatal age) had less significant respiratory disease and were fed more rapidly than late onset patients. Late onset NEC (more than 21 days postnatal age) occurred frequently in convalescing, relatively well premature infants who were still, however, of preterm postconceptional age. Relatively well premature infants with minimal respiratory disease are still at risk for NEC. Advances in neonatal care and survival of very low birthweight infants may account for a shift in prevalence to older infants who are yet of preterm postconceptional age.