Objective To investigate the effect of leptin on endoplasmic reticulum stress related protein after focal cerebral ischemia in rats. Methods Ischemia was induced by occluding the middle cerebral artery in rats brain using the filament occlusion method. Forty SD rats were randomly divided into sham operation group, cerebral is-chemia group and leptin-preconditioning group. Leptin was injected subcutaneously before occlusion of blood vessel. Longa 5 score neurological function scale, body weight and brain edema changes were measured 6 hours after MCAO, and the brain was removed to detect the endoplasmic reticulum marker protein: glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) by immunohistochemical method. Results There was no difference in the body weight changes between leptin-preconditioning group and ischemic group. In the leptin-preconditioning group, the neurological function score (1.90±0.31 vs. 2.50±0.52, P<0.05) and the degree of brain edema (3.60±0.52 vs. 7.70±0.94, P<0.001) were significantly lower than those in the cerebral ischemia group. Moreover, the expression of GRP78 in leptin-preconditioning group was significantly higher than that in ischemia group (48.69 ±5.06 vs. 35.78± 4.35, P<0.01), and the expression of CHOP was significantly lower than that of ischemia group (60.24 ±4.11 vs. 38.81±5.34, P<0.01). Conclusion Leptin can reduce the neurological deficit and may be associated with the up-reg-ulation of GRP78 protein, and down regulation of CHOP protein to weaken the endoplasmic reticulum stress caused by cerebral ischemia