The response of rats with hippocampal lesions to acute and repeated footshock stress was assessed by measurement of pituitary cyclic AMP, plasma corticosterone and plasma prolactin. Levels of pituitary cyclic AMP and plasma prolactin and corticosterone were similar in never-shocked sham controls, and never-shocked hippocampal and neocortical lesion groups. Acute first time shock markedly elevated all measured stress indices with no statistically significant differences observed among surgical groups. In rats subjected to repeated stress (one 15 min footshock session per day for 10 days) and sacrificed 24 hours after the last shock session, levels of pituitary cyclic AMP and plasma hormones were similar to levels in never-shocked shams with the exception of the hippocampal animals. The rats with hippocampal lesions had higher levels of pituitary cyclic AMP, plasma corticosterone and plasma prolactin compared to never-shocked animals. We suggest that these data reflect a hyperreactive response of the hippocampal animals to a situation previously associated with shock. Finally, rats in all surgical groups subjected to repeated stress and sacrificed immediately after the last shock session showed a diminished cyclic AMP response to the stressor as compared to first footshock session response, demonstrating a habituation to the stressor as measured by this index. No differences in habituation were observed among hippocampal, neocortical and sham groups. Plasma hormone responses did not habituate in any group. These data support the behavioral observations of hyperreactivity in hippocampal animals and indicate that hippocampal animals are able to habituate to repeated stressful stimuli.