Previous studies have suggested that spontaneous diuresis may be important to the recovery from respiratory distress syndrome in preterm infants. Daily quantification of fluid intake (1) and urine output (O) were recorded, and O/I and alveolar-arterial oxygen gradients (AaDO2) were determined for sequential eight-hour periods in 10 inborn premature infants with RDS. Sequential timed-urine-plasma collections were obtained during the first four days of life to evaluate the role of hormonal and vasoactive factors in the acute phase of RDS. Diuresis (O/I greater than 0.80) occurred at 25 to 32 hours, preceded any significant improvement in AaDO2 (which occurred at 57 to 64 hours), and was associated with a 6.2 +/- 1.4% decrease in body weight. Although there was no significant change in glomerular filtration rate, plasma AVP concentrations, or urinary excretion of AVP in the infants, there were significant decreases in both plasma concentrations and urinary excretion of 6-keto-PGF1 alpha (stable metabolite of prostacyclin) in sequential studies. These results suggest that changes in renal function or AVP may not be of primary importance in the diuresis associated with RDS, and that decreasing levels of prostacyclin, a prostaglandin that increases vascular permeability and lowers blood pressure, may have an important physiologic role.