Low birth weight (BW) is associated with an increased risk of the metabolic syndrome and cardiovascular disease in adulthood. Programed hypersecretion of glucocorticoids or reduced secretion of growth hormone have been postulated as mechanisms for this effect. However, other variables such as premature birth may confound the association of birth size with later endocrine function. To separate the effect of BW from other variables we examined basal and dynamic function of the HPA axis and GH-IGF axis in twin siblings with differing BW. Twenty pairs of same-sex healthy adult twins underwent measurement of serum cortisol before and after low-dose (1 µg) Synacthen stimulation; and plasma GH during glucose suppression and exercise stimulation. In paired statistical analysis the lower BW twin had significantly lower morning serum cortisol than their heavier BW sibling (mean intra-pair difference 60 nmol/L, 95% CI 5 to 114, P < 0.03) but no difference in peak cortisol level after ACTH. Lower BW was associated with a trend to lower baseline plasma GH and a significantly lower peak GH concentration after exercise (difference 7.6 mU/L, 95% CI 1.7 to 13.5, P = 0.01). Intra-pair differences in basal and stimulated cortisol, and basal GH also correlated significantly with the intra-pair difference in BW, demonstrating a dose-response effect of BW on HPA axis function and basal GH secretion. In a twin model that isolates BW from other confounding variables our data suggests that low BW programs individuals for reduced GH secretion and reduced basal cortisol secretion, but preservation of a cortisol secretory response to ACTH.