Antenatal treatment with glucocorticoids (GC) poses long lasting effects on endocrine and cardiovascular function. Given that leptin attenuates adrenal function and the reported sex differences in plasma leptin concentration, we hypothesized that antenatal GC will affect leptin levels and leptin modulation of adrenal function in a gender specific manner. Pregnant sheep were randomly given betamethasone or vehicle at 80 days of gestational age and offspring were allowed to deliver at term. Adrenocortical cells (ADC) were studied from male and female animals at 1.5 years of age. Plasma leptin was increased 66% in male and 41% in female GC-treated animals (p<0.05), but adrenal leptin mRNA was increased only in GC-treated males (p<0.05). While mRNA expression of adrenal leptin receptor isoforms showed gender (Ob-Ra and Ob-Rb) and treatment-dependent (Ob-Rb) differences, protein expression remained unchanged. GC-treated females showed greater plasma cortisol and greater ACTH-stimulated cortisol production (p<0.05) in ADC. Leptin exerted a greater inhibitory effect on basal and stimulated cortisol by ADC from GC-treated males (p<0.05), with no differences in females. Similarly, greater inhibitory effects on basal and ACTH-stimulated StAR and ACTH-R mRNA expression by leptin were observed in cells from GC males (p<0.05), with no changes in females. Persistent effects of antenatal GC on leptin levels and leptin modulation of adrenal function are expressed in a sex-specific manner; males are more sensitive to the inhibitory influences of leptin on adrenal function than females, this effect appears mediated by a greater inhibition of StAR and ACTH-R expression in adrenals of adult GC-treated males.