Objective To explore the protective effect and mechanism of butylphthalide on cerebral ischemia reperfusion injury in mice.Methods The cerebral ischemia reperfusion injury model was established by middle cerebral ischemia occlusion (MCAO).Thirty mice were divided into sham group,ischemia reperfusion group(I/R group) and butylphthalide group (NBP group) with 10 in each group.Neurological defect score and brain infarction volume were detected by TTC to evaluate the treatment effects of butylphthalide.Western blot was used to detect expression of RIP,RIP3 and AIF.Immunocoprecipitation (IP) was used to detect the interaction of AIF and RIP3.Immunofluorescence(IF) was used to detect the nuclear translocation and co-localization of AIF and RIP3.Results Compared with the I/R group,NBP treatment reduced the neurological defect score (I/R:(2.60 ± 0.22),NBP:(1.90 ± 0.23),t =2.18,P＜ 0.05) and brain infarction volume(I/R:(38.32±2.22) ％,NBP:(25.23±2.70) ％,t=3.74,P＜0.01).I/R elevated the expression of RIP1 and RIP3 whereas NBP significantly inhibited the expression of these two proteins (RIP1 (I/R:0.99±0.24,NBP:0.47±0.10,t=2.71,P＜0.05);RIP3 (I/R:0.52±0.17,NBP:0.15±0.04,t=2.87,P＜0.05)).I/R and NBP had no significant effects on the expression of AIF,but the IP results showed that I/R increased the interaction between AIF and RIP3 compared with the sham group.NBP alleviated the interaction between AIF and RIP3.IF results showed that the colocalization and nuclear expression of AIF and RIP3 increased after I/R whereas NBP treatment decreased the effect induced by I/R.Conclusion Butylphthalide alleviated cerebral ischemia reperfusion injury in mice through inhibiting the cell necroptosis.The mechanisms may correlate with decreasing the expression of RIP1 and RIP3 and alleviating the interaction and nuclear translocation of AIF and RIP3.