Hippocampal degeneration with aging is associated with increased hypothalamic-pituitary-adrenal (HPA) activity and, in male rats, both are attenuated by postnatal handling. Considering the important sex differences in the effects of handling and in HPA responses to stress in older rats, we have examined the effects of postnatal handling on aging in females. Female, Long-Evans rats were handled (H) during the first 3 weeks of life and later compared with nonhandled (NH) controls at various ages. Handling resulted in permanently increased hippocampal type II, glucocorticoid receptor binding. Relative to H females, NH females showed increased basal corticosterone levels in later life and hypersecreted corticosterone following stress at all ages examined. Both effects are similar to those reported in males. However, unlike males, H and NH females did not differ in corticosterone levels achieved during stress, a finding that may be related to sex-dependent effects of handling on pituitary transcortin receptors. There were no differences in hippocampal neuron density in 6-month-old animals. However, the older NH animals showed considerable neuron loss in the CA1 and CA3 hippocampal cellfields. There was little or no neuron loss in the H animals. Finally, the NH animals exhibited age-related spatial memory impairments, such that by 24 months of age the performance of the NH females was profoundly worse than that of the younger NHs and same-aged H animals. These data suggest that early handling permanently alters CNS systems that regulate hypothalamic-pituitary-adrenal (HPA) function, although the effect may depend on the gender of the animal. In both males and females, however, handling appears to prevent (or minimize) increased adrenal secretion in later life and to attenuate hippocampal cell loss and spatial memory impairments.