Female pregnant Sprague-Dawley rats were injected once daily with 40 mg/kg cocaine hydrochloride or 0.9% saline from gestational day 12 (GD 12) to GD 21. From postnatal day 21 (PND 21) to PND 60, both male and female offspring were examined for stress response. Treated male and female offspring demonstrated a diminished tolerance to stress as determined by a cold water stress test performed at PND 21, 30 and 40. Base hormonal levels of adrenocorticotropin hormone (ACTH) and corticosterone were not affected by prenatal cocaine exposure in male offspring at PND 30. However, immobilization for 1 hr caused a significant sustained elevation of corticosterone levels at both PND 30 and PND 60 in male treated offspring as compared to the control group. Plasma ACTH levels were also significantly sustained after 1 hr of immobilization at PND 60 for the cocaine-treated male offspring. These results indicate both a diminished capacity to respond to stress and an abnormal heightened reactivity of the pituitary-adrenal axis in offspring exposed to cocaine in utero.