Neonatal handling produces enduring changes in hypothalamic-pituitary-adrenal (HPA) axis activation in response to acute stress presentation. Handled rats display reduced HPA activity in response to stress, which is associated with increased hippocampal glucocorticoid receptor densities and decreased median eminence corticotrophin-releasing hormone (CRH) content. Prenatal stress (PS) also has long-term consequences on HPA responsivity to stress and related behavioral profiles. On the basis of earlier behavioral data suggesting that PS contributed to the expression of handled responses, we investigated how PS and handling might interact to affect median eminence CRH content. Groups of prenatally stressed rats and controls were subjected to a handling procedure or left undisturbed. Adult rats were killed and median eminence CRH levels were assayed as well as plasma corticosterone (CORT). PS and handling did not affect CRH content; however, handled plus PS rats exhibited significantly reduced CRH levels. Handling decreased plasma CORT concentrations, an effect that was absent in the PS rats. We contend that PS can modulate an animal's sensitivity to later environmental manipulations while producing minimal effects on its own. Researchers interested in early environmental conditions and later physiologic and behavioral responses should monitor their subjects' gestational history.