The effects of antenatal glucocorticoids on the incidence of respiratory distress syndrome (RDS) in 128 premature human infants were studied. There was a significant reduction in the incidence of RDS in the betamethasone-treated infants to 8.7% compared to an incidence of 22.6% in the saline-treated controls and 25.0% in infants whose mothers received methylprednisolone. The effectiveness of betamethasone in reducing RDS was limited to premature infants delivered to mothers with intact fetal membranes and with an initial L/S lecithin/sphingomyelin ratio less than 2.0. The time between administration of the glucocorticoid and delivery did not significantly affect the incidence of RDS. The failure of methylprednisolone to reduce the development of RDS in premature infants suggested its potential use in maternal therapy during pregnancy with minimal effects on fetal maturation.