The present study has been designed to expound the significance of cyclic adenosine diphosphoribose receptor activation in ischemic preconditioning induced reversal of ischemia and reperfusion induced cerebral injury in mice. Bilateral carotid artery occlusion of 17 min followed by reperfusion for 24 h was employed in present study to produce ischemia and reperfusion induced cerebral injury in mice. Cerebral infarct size was measured using triphenyltetrazolium chloride staining. Memory was evaluated using Morris water-maze test. Rota-rod test was employed to assess motor incoordination. Bilateral carotid artery occlusion followed by reperfusion produced cerebral infarction and impaired memory and motor co-ordination. Three preceding episodes of bilateral carotid artery occlusion for 1 min and reperfusion of 1 min (ischemic preconditioning) prevented markedly ischemia-reperfusion-induced cerebral injury measured in terms of infarct size, loss of memory and motor coordination. 8-Bromo-cyclic adenosine diphosphate ribose (2 mg/kg, ip), an antagonist of cyclic ADP-ribose receptor, attenuated the neuroprotective effect of ischemic preconditioning. It is concluded that neuroprotective effect of ischemic preconditioning may be due to the adenosine diphosphoribose receptor activation.