Objective To investigate the neuroprotective effect of U0126 in ischemic stroke and the underlying role of U0126-mediated T cells.Methods Adult male C57BL/6J wild-type mice and adult male severe combined immunodeficiency (SCID) mice were randomly divided into sham group, sham+U0126 (2 g/L) group, middle cerebral artery occlusion (MCAO) group, and MCAO+U0126 group, with 10 wild-type mice and 10 SCID mice in each group. A mouse model of MCAO was constructed by the suture method, and the suture was removed after 60 min of ischemia to restore blood flow. The effects of U0126 on the size of cerebral infarction and the proliferation of spleen cells were compared between the mice with and without immune deficiency.Results U0126 significantly reduced cerebral infarction volume (P<0.05) and the inhibition of spleen cell proliferation (P<0.05) in the wild-type mice with cerebral ischemia-reperfusion. By contrast, U0126 significantly increased cerebral infarction volume (P<0.05) in the SCID mice with T cell deficiency; after using concanavalin A to stimulate T cell proliferation, the protective effect of U0126 was significantly restored (P<0.05), suggesting that T cells may be the target of U0126.Conclusions U0126 may exert a neuroprotective effect against ischemic stroke by inhibiting the ERK1/2 signaling pathway and selectively promoting T cell proliferation.