The presence of insulin receptor in the hippocampus suggests that this organ is a target for insulin. However, unlike the classic peripheral insulin target tissues such as adipocyte, muscle and liver, where the primary function of insulin is to regulate glucose homeostasis, insulin in the central nervous system (CNS) exhibits more diverse actions, most of which have not been clearly understood. A direct role of hippocampal insulin receptor signaling in improving cognitive functions, including learning and memory, and the association of insulin receptor deterioration with brain degenerative dementia (e.g., Alzheimer's disease) have attracted increasing interest. Additionally it has been shown that insulin can be a neuroprotective agent against memory loss induced by ischemia, lesions and some pharmacological agents. In the present study we evaluate the hypothesis that the bilateral intra CA1 insulin injection can protects against stress-induced memory deficit. Chronic restraint stress (2h per day x 7 days) significantly impaired spatial performance in Morris water maze and elevated serum corticosterone level. Intrahippocampal insulin microinjection was done 15-20 min before every stress episode. Insulin in low dose (0.5 MU) had no significant effect on memory deficit induced by stress. But in higher doses (6 and 12 MU) insulin protects animals against the deleterious effect of stress. Insulin alone daily injection had no effect on water maze performance. These results suggest that spatial learning and memory is compromised during chronic stress and insulin may protect against this effect.