Background: Secondary HLH is closely related to EBV infection, protein changes in plasma exosomes may be related to the pathogenesis of HLH patient. In recent years quantitative proteomic has been used to clarify the relationship between basic medicine and clinical medicine. Methods: Exosomes were isolated from plasma samples of a HLH patient and his twin brother. Plasma samples were classified into three groups according to the clinical presentation, namely T1 (the acute HLH), T2 (during pharmacological treatments), Ctr (the healthy control). Herein, we used TMT-based LC-MS/MS platform to identified and characterized HLH signatures before and during pharmacological treatments. Results: Exosomes’ marker proteins- CD63, TSG101, HSP70 were identified by western blotting. Through GO analysis and KEGG analysis, we found that the signaling pathways and functions enriched by differentially expressed genes are very different. We focus on describing? the significantly up-regulated proteins-MSN, HSPA8, CD163, and the significantly down-regulated proteins- PLG, FGG, F2. The significant changes of these factors are related to the deterioration of the disease Conclusion: Our exploratory study shows that the clinical symptoms and pathophysiological changes of HLH driven by EBV might be reflected in patients’ plasma exosomes. Plasma exosome proteomics provides new highlightinsights for into exploring the diagnostic and therapeutic biomarkers of HLH.