<i>Background:</i> In premature infants there is no universally accepted definition of anemia requiring transfusion. We designed the present investigation to study the effects of red blood cell transfusion (based on simple transfusion rules) on weight gain, energy metabolism, and heart rate in otherwise healthy preterm infants. <i>Patients and Methods:</i> We measured oxygen consumption (VO2), respiratory quotient (RQ) and energy expenditure (EE) by 4-hour indirect calorimetry, and assessed weight gain over 7 days and heart rate in 12 infants with late anemia of prematurity before and after red blood cell transfusion (10 ml/kg). At the time of transfusion, postmenstrual age was 38 ± 1 weeks (mean ± SEM), body weight 2.14 ± 0.13 kg, and hemoglobin concentration 7.7 ± 0.3 g/dl (range: 5.5-9.2). <i>Results:</i> Red blood cell transfusion increased the hemoglobin concentration by 3.8 ± 0.5 g/dl, but had no significant effect on weight gain (15.4 ± 2.4 vs. 13.8 ± 1.8 g/kg/day), V02 (8.7 ± 0.3 vs. 8.7 ± 0.3 ml/kg/min), minimal VO2 (7.2 ± 0.3 vs. 7.7 ± 0.4 ml/kg/ min), RQ (0.96 ± 0.02 vs. 0.95 ± 0.02), EE (50 ± 2 vs. 51 ± 2 kcal/kg/day), and heart rate (160 ± 3vs.158 ± 3min-1). <i>Conclusion:</i> We conclude that oxygen supply and energy metabolism were not compromised in the anemic preterm infants at the time of red blood cell transfusion.