Objective: To investigate the effect of endogenous histamine on ischemic preconditioning induced cerebral ischemic tolerance in rats. Methods: Wild-type (WT) mice and histidine decarboxylase knock-out (HDC-KO) mice were preconditioned by bilateral carotid artery occlusion (BCCAO) for 6,10,or 14 min and reperfused for 48 h,then subjected to permanent BCCAO and the survival time of WT and HDC-KO mice subjected to permanent BCCAO was observed.Histamine levels in the hypothalamus,hippocampus,striatum and cortex at 0.5 h,5 h or 48 h after 10 min BCCAO were determined with high-performance liquid chromatography. Results: Ten minutes ischemic preconditioning significantly prolonged the survival time of WT mice subjected to permanent BCCAO.However,in HDC-KO mice,the ischemic tolerance was not induced with 10 min preconditioning.The histamine levels at 0.5 h or 48 h increased after 10 min preconditioning,but not at 5 h. Conclusion: Endogenous histamine in brain may be an essential mediator in ischemic preconditioning induced cerebral ischemic tolerance.