After blood loss, adults promptly increase production of erythropoietin(Epo), and the subsequent acceleration in erythropoiesis restores the red blood cell mass. Recombinant Epo has recently been used as a means of reducing transfusion requirements of preterm neonates. It is unclear whether preterm infants who sustain large phlebotomy losses respond by increasing serum Epo concentrations. To assess this, we measured Epo levels before and after blood transfusions in sick preterm infants during the first two weeks of life. Phlebotomy losses were monitored in 11 mechanically-ventilated preterm infants with birth weights 1057±167 grams (range 647-2632 grams) and gestational ages 27.2±1.1 weeks (24-36 weeks) prior to and following their first transfusions. Epo concentrations were measured when phlebotomy losses reached 5, 10, and 15 mL/kg, and again 24 hours following transfusion, for a total of two transfusions per infant. Epo concentrations declined in all patients, despite increasing phlebotomy losses. Prior to the first transfusion, Epo concentrations were 68.9±36.2 mU/mL (range 0-205 mU/mL) at 5 mL/kg blood out, decreasing to 17.4±8.9 mU/mL at 10 mL/kg, and 4.8±2.6 mU/mL at 15 mL/kg blood out. Following the first transfusion, Epo concentrations were 22.2±16.8 mU/mL at 5 mL/kg blood out, 14.8±10.5 at 10 mL/kg blood out, and 5.2±2.8 mU/mL at 15 mL/kg blood out. Epo concentrations declined even further to 3.0±1.0, 3.9±1.7, and 3.5±1.4 mU/mL at 5, 10, and 15 mL/kg blood out, respectively, following the second transfusion. In no instance did Epo concentrations increase in any of the infants. We conclude that ill, preterm infants fail to increase Epo production in the face of significant blood loss. Although the mechanistic explanation for this failure is unclear, it likely contributes to the transfusion requirements of this population.