To explore the mechanism of the protective effect of Shexiang Huangqi(SXHQ) compound dropping pills on cerebral ischemia reperfusion injury(CIRI) rat models.Methods:A total of 54 male SD rats were randomly divided into a sham operation group，a model group，and an SXHQ group，with 18 rats in each group.Middle cerebral artery occlusion(MCAO) models were prepared by ZeaLonga's suture-occluded method.SXHQ compound dropping pills were given 3 d before modeling and continued for 5 days.Before tissue collection，neurological function scoring was conducted in rats.The infarct size of MCAO reperfusion rats was measured by 2,3,5-triphenyltetrazolium chloride(TTC) staining.The hippocampal tissues of rats were separated to observe pathological changes in them by hematoxylin and eosin(HE) staining.The relative and absolute quantitative isotope labeling(iTRAQ) proteomics method was used to analyze the hippocampal tissues of rats after the intervention to screen out the differentially expressed proteins.Then，the following bioinformatics analyses were conducted on the differentially expressed proteins：expression level hierarchical clustering，gene ontology(GO)，Kyoto encyclopedia of genes and genomes(KEGG)，and protein-protein interaction(PPI).Results:Compared with the model group，neurological severity score was significantly improved in the SXHQ group，with reduced white infarction area in brain tissues，decreased neuromyopathy number in the CA3 area of hippocampal tissues and significantly improved morphology，as well as increased CD44 and HSP27 expression levels(P<0.05).Compared with the sham operation group，there were 181 different proteins in the model group.Compared with the model group，there were 121 different proteins in the SXHQ group.Among them，Ca3，Hspb1，Htr1a，Aldh1a1，Cd44，Map1a，Pnkd，Cd99l2，Ubxn8，and Alb were significantly changed in MCAO/R rats，significantly reversed after SXHQ intervention.The life processes involved were mainly relevant to immune inflammation.Conclusion:iTRAQ can be effectively applied for tissue protein identification and quantitation，while bioinformatics analysis can be utilized to look for potential therapeutic targets for Shexiang Huangqi compound dropping pills in intervening CIRI，which might be related to immune inflammation mechanisms.