It is well established that stress in early life can alter the activity of the hypothalamus-pituitary-adrenal (HPA) axis, but most studies, to date, have focused on HPA reactivity in response to a single acute stress. The present study addressed whether stress in pregnant mice could influence the adaptive responses of their offspring to chronic stress. Male offspring were exclusively used in this study. Elevated plus maze (EPM) tests revealed that 14 days of repeated restraint stress (6 h a day; from P50 to 63) significantly increased anxiety-like behavior in maternally stressed mice. NBI 27914, a CRH (CRH) receptor antagonist completely eliminated anxiety-related behaviors in a dose-dependent manner, indicating an involvement of hyperactive CRH system. In accordance with increased anxiety, CRH contents in the hypothalamus and amygdala were significantly higher in these mice. In spite of an increased basal activity of the CRH-adrenocorticotropic hormone (ACTH) system, the combination of chronic prenatal and postnatal stress resulted in a significant reduction of basal plasma corticosterone (CORT) level, presumably due to a defect in adrenal function. Along with alterations in hypothalamic and hippocampal corticosteroid receptors, it was also demonstrated that a dysfunction in negative feedback inhibition of the HPA axis could be deteriorated by chronic stress in maternally stressed male mice. Taken together, these results indicate that exposure to maternal stress in the womb can affect an animal's coping capacity to chronic postnatal stress.