A term (39-wk-old) male neonate exhibited respiratory distress and anuria within 2 days of birth. The patient was diagnosed with pulmonary hypertension, polycystic kidney disease, and heart failure; his initial B-type natriuretic peptide concentration was 2460 pg/ml. After minimal response to loop diuretics, the patient was given an infusion of nesiritide 0.01 microg/kg/minute, with no loading dose. Urine output increased over 400%, and cardiac function improved. Nesiritide was titrated to 0.03 microg/kg/minute with no hypotension, decreased renal function, or adverse cardiac sequelae over the next 6 days. No subsequent changes in cardiac function occurred during the infant's stay in a progressive care unit, but he died at age 5.5 months due to sepsis. This case report demonstrates the successful first use of nesiritide therapy in a neonate with renal disease. Further studies are warranted to evaluate the safety and administration of this agent in the neonatal patient population.