Objective: To assess the long-term outcome of brain structure in preterm infants, at an average age of 12 years, who received a red blood cell transfusion for anemia of prematurity. Design: As neonates, this cohort of infants participated in a clinical trial in which they received red blood cell transfusions based on a high pretransfusion hematocrit threshold (liberal group) or a low hematocrit threshold (restricted group). These 2 preterm groups were compared with a group of full-term healthy control children. Setting: Tertiary care hospital. Participants: Magnetic resonance imaging scans for 44 of the original 100 subjects were obtained. Intervention: Liberal vs restricted transfusion. Main Outcome Measures: Intracranial volume, total brain tissue, total cerebrospinal fluid, cerebral cortex and cerebral white matter volume, subcortical nuclei volume, and cerebellum volume. Results: Intracranial volume was substantially smaller in the liberal group compared with controls. Intracranial volume in the restricted group was not different from controls. Whole-cortex volume was not different in either preterm group compared with controls. Cerebral white matter was substantially reduced in both preterm groups, more so for the liberal group. The subcortical nuclei were substantially decreased in volume, equally so for both preterm groups compared with controls. When sex effects were evaluated, the girls in the liberal group had the most significant abnormalities. Conclusion: Red blood cell transfusions affected the long-term outcome of premature infants as indicated by reduced brain volumes at 12 years of age for neonates who received transfusions using liberal guidelines.