Objective To investigate the effect of exogenous calcitonin gene related peptide (CGRP) and nerve growth factor (NGF) on the expression of cyclic AMP response element binding protein (CREB) and phosphorylated CREB (p-CREB) in rat hippocampus during focal cerebral ischemia/reperfusion (I/R). Methods Focal cerebral ischemia/reperfusion model was set up by occlusion of the right middle cerebral artery using the intraluminal suture method.The expression of CREB and p-CREB in the right hippocampus were detected with immunohistochemistrical SABC method and Western blotting. The immunoreactive positive products were analyzed by image analysis system. Results The expression of CREB decreased in I/R group as compared with sham group in right hippocampus, but the expression of p-CREB was higher in I/R group than that in sham group（P<0.05）. The average absorbence (A) of CREB and p-CREB positive products in CGRP group and NGF group were higher than that in I/R group（P<0.05）. Furthermore, the expression of CREB and p-CREB was even higher under the combined treatment of CGRP and NGF than that in CGRP group and NGF group respectively（P<0.05）.Conclusion CREB may be involved in the mechanism of protective effect of CGRP and NGF on ischemic neurons. CGRP and NGF may have coordinated protective effect on the isc