Objective To evaluate the.effect of hypothermia on hippocampal endoplasmic reticulum stress during global cerebral ischemia-reperfusion (I/R) in rats. Methods Fifty-four healthy male Sprague-Dawley rats, weighing 280-320 g, were randomly divided into 3 groups (n = 18 each) using a random number table: sham operation group (group S), global cerebral I/R group (group I/R) and hypothermia group (group H). Cardiac arrest was induced with transoesophageal cardiac pacing followed by cardiopulmonary resuscitation to establish the global cerebral I/R model in anesthetized rats in I/R and H groups. In group H, the body temperature was cooled down to 32-34 ℃ within 10 min starting from the beginning of reperfusion, and maintained at this level for 4 h, and the body temperature was maintained at 36-37 ℃ in the other groups. Neurological deficit was scored at 24 h of reperfusion, and the rats were then sacrificed, and bilateral hippocampi were immediately removed for determination of glucose-regulated protein 78 (GRP78) and caspase-12 expression (by Western blot). The brains were removed and cut into sections which were stained with haematoxylin and eosin to examine the morphological structures of pyramidal cells in hippocampal CA1 region (under microscope). Immunohistochemical staining was used to count GRP78 and caspase-12 positive cells. Results Compared with group S, the neurological deficit score was significantly increased at 24 h of reperfusion,the number of normal pyramidal cells in hippocampal CA1 region was decreased, the expression of GRP78 and caspase-12 was up-regulated,and the number of GRP78 and caspase-12 positive cells was increased in I/R and H groups (P<0.05). Compared with group I/R,the neurological deficit score was significantly decreased at 24 h of reperfusion,the number of normal pyramidal cells in hippocampal CA1 region was increased, the expression of GRP78 and caspase-12 was down-regulated,and the number of GRP78 and caspase-12 positive cells was decreased in group H (P<0.05). Conclusion Hypothermia can attenuate global cerebral I/R injury through inhibiting hippocampal endoplasmic reticulum stress in rats.