Objective: To compare effectiveness between single and multiple courses of antenatal steroids in preterm births and determine adverse effects attributable to multiple courses. Methods: We studied retrospectively the neonatal outcomes of infants who weighed 1750 g or less at birth between January 1990 and December 1997. Infants exposed to a single course were compared with those exposed to two or more courses of antenatal steroids, with respect to various perinatal outcome variables. Results: Ninety-three neonates were exposed to two or more courses of antenatal steroids and 261 neonates had been given single courses. The mean (± standard deviation) gestational age (29.6 ± 2.8 weeks compared with 28.7 ± 2.7 weeks; P = .007) and birth weight (1252 ± 321 g compared with 1159 ± 339 g; P = .013) were significantly higher among neonates exposed to multiple courses. There were no significant differences between groups in perinatal outcomes; however, those exposed to multiple courses had a significantly lower rate of respiratory distress syndrome (RDS) (17 [18%] compared with 107 [41%]; P ≤ .001) and surfactant use (40 [43%] compared with 149 [57%]; P = .02). Adjusting for confounding variables, multiple courses of steroids were significantly associated with a 65% reduction in the incidence of RDS (odds ratio 0.35; 95% confidence interval = 0.18, 0.70; P = .003). Conclusion: Compared with single courses, multiple courses of antenatal steroids reduced significantly the incidence of RDS with no apparent increase in neonatal sepsis or disturbances in fetal growth.