To further characterize the place for furosemide in the treatment of newborn infants with respiratory distress syndrome requiring mechanical ventilation, we conducted a blinded, prospective study comparing early prophylactic use (1 mg/kg every 12 hours for four doses beginning at 24 hours of age) with prn use of this drug. Prophylactic administration of furosemide produced no beneficial effect on any measure of pulmonary function compared with use of this drug as needed (prn). However, patients receiving the prophylactic furosemide regimen were found to have more rapid postnatal weight loss, higher pulse rate, and greater sympathomimetic drug requirement during the period of diuretic administration. Patients in the prophylactic group did not demonstrate the moderate expansion in plasma volume between 48 and 96 hours of age seen in the control group. These data suggest that the prophylactic regimen produced an undesirable degree of volume depletion. Further studies should be conducted to develop objective criteria for the selection of the subgroup of patients with respiratory distress syndrome who may benefit from furosemide.