Context: Experimental studies in animals show that adverse prenatal environments lead to lifelong alterations in the activity of the hypothalamic-pituitary-adrenal axis, which mediates the stress response through secretion of glucocorticoid hormones. The extent to which such prenatal hypothalamic-pituitary-adrenal axis adaptations occur in humans is unknown. Objective: The objective of the study was to determine whether smaller but otherwise healthy term babies are more likely to demonstrate increased glucocorticoid responses to psychological stress in childhood. Design and Participants: This was a cross-sectional study of 68 boys and 72 girls (aged 7-9 yr) who have been followed up since 12 wk gestation when their mothers took part in a study of healthy children born in Southampton, United Kingdom. Main Outcome Measure: Salivary cortisol responses to psychological stress were measured. Results: In boys, birth weight was inversely related to salivary cortisol responses to stress (r = -0.56, P < 0.001) but not morning cortisol levels, whereas in girls, morning peak cortisol was inversely related to birth weight (r = -0.36, P < 0.05). These associations were independent of gestational age and potential confounding factors including obesity, social class, and educational achievement. Conclusions: This study suggests that processes occurring during fetal life, resulting in smaller newborns, have a lasting effect on adrenocortical responses to stress in boys and on basal adrenocortical activity in girls. Given the known associations between small alterations in adrenocortical activity and features of the metabolic syndrome such as raised blood pressure and glucose intolerance, these effects warrant further investigation of their potential impact on the future health of prepubertal children.