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Supplemental Digital Content is available in the text, Exosomes are nanometer-sized vesicles with intercellular communication functions, and their encapsulated proteins may participate in the pathological process of neurodegenerative disorders. The aim of this study was to identify the protein changes of serum exosomes in Parkinson disease (PD) patients with different disease progress types, and to identify potential biomarkers. The exosomes of PD patients with different severity and healthy control group were isolated from serum. The exosome proteins were analyzed by mass spectrometry with label-free quantitative proteomics. A total of 429 proteins were identified, of which 14 were significantly different in mild and severe PD patients. The expression levels of 7 proteins, including pigmented epithelium-derived factor, afamin, apolipoprotein D and J, were significantly increased in PD patients. The expression levels of 7 proteins, including complement C1q and protein Immunoglobulin Lambda Variable 1-33 (IGLV1-33)Cluster -33, were decreased in PD patients. These differentially expressed proteins were analyzed by gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis, which confirmed that the interaction between prion diseases and ECM receptors was the most significant pathways of enrichment. The changes of proteins and pathways may be related to the pathophysiological mechanism of PD. Therefore, some of these proteins could be considered as potential biomarkers for early PD diagnosis.