BACKGROUND: Red blood cell (RBC) transfusions are crucial for the care of very-low-birth-weight (VLBW) infants. These infants frequently require multiple, small-volume RBC transfusions, with potential exposure to multiple donors. Optimal protocols provide dedicated RBC units to reduce exposures and avoid RBC wastage. STUDY DESIGN AND METHODS: This study was a retrospective, single-institution review of RBC transfusions in VLBW infants. The RBC volume transfused during the entire hospitalization (VTH) and that transfused at 35 days were determined for all infants, 401 to 1250 g at birth, admitted to a Level III neonatal intensive care unit from January 1, 2000, through December 31, 2002. Multivariable models identified perinatal factors associated with volume transfused. RESULTS: The 640-infant cohort had a median birth weight (BW) of 818 g and gestational age (GA) of 26 weeks. Most infants (546 or 85%) required at least one RBC transfusion. Median number of RBC transfusions was 3 (range, 0-30) and median volume transfused was 82 mL (range, 9-737 mL). Of 328 infants who received all transfusions within a 35-day period, only 5 (1.5%) required at least 200 mL. VTH was inversely related to BW and GA. Multivariable models identified BW, GA, age at first transfusion, and use of inotropes as variables associated with higher volume transfused. CONCLUSION: Few VLBW infants use an entire RBC unit. One dedicated unit shared by two or more infants should meet their transfusion needs. GA, BW, and markers of illness severity predict increased RBC volume requirements. © 2006 American Association of Blood Banks.