Placental 11-hydroxysteroid dehydrogenase-2 (11HSD2) limits fetal glucocorticoid exposure and is associated with physiological stability in the premature newborn infant. Antenatal betamethasone alters 11HSD2 activity and confers sex-specific advantages in neonatal outcome. We investigated the influence of betamethasone and sex on 11HSD2 activity, neonatal adrenal function and clinical course in 24-36 week gestation neonates from birth to day 5 of life. Univariate analyses demonstrated an interaction between timing of betamethasone exposure and sex for 11HSD2 activity rate (p=0.02) and umbilical arterial cortisol (p=0.01). For infants born <72 hours following antenatal betamethasone, females had higher 11HSD2 activity (p<0.01) and umbilical arterial cortisol (p=0.01) than males. Females born <72 hours of betamethasone exposure had higher day 1 urinary cortisol if exposed to perinatal stress than males (p<0.01). For infants born < 72 hours after betamethasone exposure 11HSD2 activity was negatively correlated with CRIBII score (r =-0.79 p=0.01) and positively correlated with mean arterial blood pressure (r =0.8 p=0.01) only in females. Sex-specific placental 11BHSD2 auto-regulation following antenatal betamethasone exposure may limit adrenal suppression in females influencing physiological stability following preterm birth. A lack of adjustment in 11HSD2 and adrenal response may contribute to the increased incidence of poor outcome observed in preterm males.