Necrotizing enterocolitis (NEC) is a disease primarily of prematurity characterized by partial or entire gut necrosis and is associated with significant mortality and morbidity. Recent studies report that approximately 25% to 35% of very low-birth-weight infants less than 1500 g receiving packed red blood cell transfusions develop temporally associated NEC, known as transfusion-related NEC (TR-NEC). Although there are many known risk factors for NEC, this article focuses on 3 contributing factors: packed red blood cell transfusions, enteral feedings, and gastrointestinal immaturity. Previous data suggest that these factors may interact to affect neonatal intestinal tissue oxygenation, which may lead to tissue ischemia, resulting in intestinal injury. This article presents a conceptual framework that combines current theoretical perspectives for TR-NEC, and reviews previous research examining related variables and how their interaction may increase the risk for TR-NEC development. In addition, incorporation of the proposed framework to guide future research and nursing care in this area is discussed.