Cyclic AMP response element-binding protein (CREB) is a transcription factor that has been implicated in the activation of a number of genes. We reported that CREB levels decline following a severe hypoglycemic episode in the hippocampus and cortex in the male rat brain. The present experiment was undertaken to investigate whether 17beta-estradiol prevents the decline in CREB-immunoreactive cells following seizure in female rats. Rats were divided into four groups: ovariectomized (OVX), ovariectomized and insulin-treated (OVX-I), estrogen-replaced (E2), and estrogen-replaced and insulin-treated (E2-I). Generalized seizures were induced by injections with insulin (12.5 IU/kg, intraperitoneally) and animals were recovered by administration of glucose within 5 min of the occurrence of seizure. Control animals were injected with saline instead of insulin. All animals were perfused 90 min after recovery and the brains were processed for CREB immunoreactivity. CREB-positive neurons were counted using a computer-assisted program. Insulin treatment of OVX rats caused a significant decline in CREB-positive neurons in the CA1, CA3, and dentate gyrus compared to OVX rats. Estrogen treatment of OVX rats significantly increased CREB-positive neurons in the CA1 and dentate gyrus and attenuated the insulin-induced decline of CREB-positive neurons in all three regions compared to OVX rats. In conclusion, estrogens appear to induce CREB expression and attenuate its decline in the hippocampus following a severe hypoglycemic episode.