Objective To explore the expression of glutamate receptor interacting protein (GRIP) after ischemia-reperfusion in the rat brain. Methods Seventy-two male Sprague Dawley rats were randomly divided into 6 ischemia-reperfusion groups and sham groups with 6 rats per group. Middle cerebral artery occlusion (MCAO) was achieved with the use of an intraluminal filament to occlude the left middle cerebral artery, and reperfused 2 hours later. At the 1st, 3rd, 6th, 12th, 24th and 72th hour after reperfusion or sham operation, the rats from each group were decapitated. Immunohistochemistry and double immunofluorescence were used to observe the distribution of GRIP in the cortex and also its relationship with glutamate receptor 2 (GluR2). Results Compared with the sham-operated group which showed few positive neurons, GRIP positive neurons increased obviously from 3 hours after ischemia-reperfusion in the ischemic penumbra cortex, mainly on the dendrites at the early stage and moved to the cell body lately. Double immunohistochemical staining showed that the GRIP positive cells were co-stained with GluR2 neurons. Conclusion GRIP increased and accelerated to transfer GluR2 to the membrane after ischemia-reperfusion which may protect the neurons in the penumbra zone from the AMPA receptor mediated excitotoxic injury.