Objective:To observe the effect of ovariectomy on the protein expression of CREB in model of MCAO rats and the intervening influence of “Zuogui Pills”. Methods64 female wistar rats were randomly divided into 4 groups and each group has 16 rats as following:the sham operation group,the cerebral ischemia group,the cerebral ischemia with ovariectomy group and the cerebral ischemia with ovariectomy given Chinese medicine group. Middle cerebral artery occlusion (MCAO) was operated in rats except the rats in sham operation group,and ischemia-reperfusion were used 2 hours after MCAO. The cerebral ischemia with ovariectomy group was bilateral ovary removed 10 days before the MCAO operation. The cerebral ischemia with ovariectomy given Chinese medicine group was also bilateral ovary removed 10 days before the MCAO operation and given“Zuogui Pills”gavage (1.62g/kg) one times a day from 3 days before MCAO surgery for consecutive 10 days. Immunohistochemistry and western blotting were used to assess the level of CREB.  Results:Compared with the sham operation group, the expression of CREB increased (P<0.05)；compared with the cerebral ischemia group, the expression of CREB in the cerebral ischemia with ovariectomy group decreased obviously (P<0.05)；compared with the cerebral ischemia with ovariectomy group, the expression of CREB in the the cerebral ischemia with ovariectomy given Chinese medicine group increased obviously (P<0.05).  Conclusion:CREB expression was increased after cerebral ischemia may be a defensive response of body. Sex hormone deprivation can significant aggravate cerebral ischemia reperfusion induced brain injury and down-regulation of CREB expression. “Zuogui Pills ” can against the impairment,which is likely achieved by activation of CREB,which showed that “Zuogui Pills ” of traditional Chinese medicine may have hormone like effect,and might promote the recovery of ischemic brain injury through up-regulation of CREB expression.