We conducted a multicenter controlled trial to test the hypothesis that high-dose intravenous immune globulin (HDivIG) therapy can modulate bilirubin production and reduce the frequency of exchange transfusions in newborn infants with Rh hemolytic disease. Thirty-four patients with Rh incompatibility proved by positive direct antiglobulin test (Coombs test) results were randomly assigned to receive conventional treatment including phototherapy, with or without additional HDivIG therapy at 500 mg/kg given for a 2-hour period as soon as the diagnosis was established. Exchange transfusions were performed if serum bilirubin concentrations exceeded the modified curves of Polácek by more than 2 mg/dl. Two patients were excluded because of protocol violations. The results in 32 infants were analyzed. In the HDivIG group, 2 (12.5%) of 16 children required exchange transfusions, whereas it became necessary in 11 (69%) of 16 children in the control group (p less than 0.005). Bilirubin levels in the HDivIG group were lower despite reduced frequency of exchange transfusions. No side effects of HDivIG treatment were observed. We conclude that HDivIG therapy by a yet unknown mechanism reduces serum bilirubin levels and the need for blood exchange transfusions in children with Rh hemolytic disease.