Forty-four infants were treated with hydrocortisone or a lactose placebo in a controlled study to evaluate the ability of postnatally administered hydrocortisone to alter the course or outcome in infants with the Respiratory Distress Syndrome (RDS). No significant effect on PaO2, PaCO2, [H+], percent ambient oxygen needed, A-aDO2 gradients, need for assisted ventilation, or survival was demonstrated. Plasma corticosteroids during the 72-hour period after administration showed significant differences between the hydrocortisone- and placebo-treated infants. Additional analysis of plasma corticosteroid levels in 24 RDS infants versus 10 control prematures failed to demonstrate any endogenous deficiency of corticosteroids in infants with RDS. Although no immediate detrimental effects of the therapy were seen, the postnatal use of corticosteroids did not appear to carry any obvious benefit for the infant with RDS.