We studied the acute effects of increasing hemoglobin concentration and hematocrit on the pulmonary and systemic circulations of nine infants with large left-to-right shunts. After isovolemic exchange transfusion, which was designed to raise hemoglobin but keep blood volume constant, a consistent rise in systemic and pulmonary vascular resistances occurred. This rise was comparable to those previously found in isolated circulations showing a linear relation between hematocrit and loge of the vascular resistance. These changes in resistance were accompanied by decreases in systemic and pulmonary blood flow and a marked decline in left-to-right shunt. Despite the decrease in systemic blood flow, there was no decline in systemic oxygen transport, and there may have been a marginal decrease in left ventricular stroke work. These observations help explain why the newborn with a large ventricular septal defect and a high hemoglobin concentration does not have clinical signs of a large left-to-right shunt, and also suggest that the postnatal decline in hematocrit has a substantial role in the normal fall in pulmonary vascular resistance after birth.