The effects of betamethasone on surfactant composition and neonatal adrenal function were compared with placebo in a double-blind study, which included 74 patients at risk for premature delivery. The overall incidence of respiratory distress syndrome was low, and no differnce was observed between the betamethasone and placebo groups. The phospholipid pattern (lecithin/sphingomyellin ratio, acetone precipitated lecithin, phosphatidylinositol/sphingomyelin ratio, and phosphatidylglycerol/sphingomyelin ratio) from gastric aspirates of newborn infants was similar in the betamethasone and placebo groups, suggesting a similarity in lung surfactant. The responsiveness of the adrenal cortex of the newborn infants, evaluated by a 2-hr adrenocorticotropic hormone test at the age of 24 hr, did not differ between infants whose mothers had received either betamethasone or placebo. The low incidence of respiratory distress syndrome in the betamethasone and placebo groups was ascribed in part to a high incidence of prolonged rupture of fetal membranes. Our results do not exclude the possibility that antenatal maternal administration of betamethasone could prevent respiratory distress syndrome in other defined high-risk infants.