The purpose of this study was to determine an association between packed red blood cell (PRBC) transfusions for anemia and necrotizing enterocolitis (NEC) in a subset of stable, growing, premature neonates. As part of a survey of current clinical practices over a 17-month period from June 1999 to October 2000, a chart review was performed to determine the relationship between elective PRBC transfusions and the occurrence of NEC. Demographic data were tabulated and compared between the NEC patients with a prior history of immediate blood transfusion (within 48 hours of onset of symptoms) and those NEC patients without a prior history of immediate blood transfusion. A total of 908 (inborn) neonatal admissions had received 751 PRBC transfusions during the study period; of these, 17 patients (1.8%) had developed radiographic, clinical, or surgical signs of NEC. Six cases of NEC (35%; six of 17 patients) were associated with PRBC transfusions (0.8%; six of 751 transfusions). The transfusion-associated NEC group developed presenting signs within 22 +/- 5 hours (median, 19; range, 12 to 38) of a PRBC transfusion at a mean age of 32 +/- 7 days. In contrast, the non-transfusion-associated NEC group (n = 11) had onset of NEC at a mean age of 12 +/- 7 days ( P < 0.05) after 185 +/- 91 hours (median, 180; range, 96 to 312; P < 0.02] of a transfusion. Prior to the onset of NEC, all of the neonates in the transfusion-associated NEC group were stable, growing, not ventilated, receiving full enteral feedings, and had no other active medical problems except anemia (hematocrit, 24 +/- 3%). In contrast, the nontransfusion NEC group was more often ventilated, was receiving < 50% of fluids by mouth, had lower Apgar scores, and was transfused for an average hematocrit of 37 +/- 7% ( P < 0.05). There was no significant difference in the type, storage, volume, or preservative used between the blood products in the two groups. We identified an unanticipated relationship between late-onset NEC in stable, growing, premature neonates who were transfused electively for anemia of prematurity.