The management of (Rhesus) hemolytic disease of the fetus and newborn includes intrauterine transfusions to prevent the development of hydrops, treatment of the possible hyperbilirubinemia in the immediate postnatal period, and treatment of late anemia. Low levels of serum erythropoietin due to suppression of the bone marrow by multiple intrauterine transfusions is a suggested mechanism for this anemia. The aim of our study was to test whether recombinant human erythropoietin reduced the need for erythrocyte transfusions in these infants. Twenty infants with Rhesus isoimmunization were blindly randomized to treatment and control groups at the 2nd wk of life. The number of intrauterine and exchange transfusions and demographic data were similar in both groups. The infants in the treatment group received recombinant human erythropoietin, s.c. 200 U/kg of body weight three times a week for a period of 6 wk, whereas the infants in the control group received a placebo for the same period. In the treatment group, the mean number of erythrocyte transfusions was significantly lower than that of the control group (1.8 versus 4.2). The reticulocyte counts and Hb levels rose earlier in the treatment group. The platelet and neutrophil counts were similar in both groups throughout the study. This study demonstrates that recombinant human erythropoietin treatment decreases the need for erythrocyte transfusions in the late anemia of infants with Rh isoimmunization. Considering the risks of blood transfusions, this decrease in the donor exposure is worthwhile.