Aim Atherosclerosis (As) primarily involves the systemic arteries. The luminal surface of the artery is directly exposed to blood and is susceptible to active blood substances. Exosomes contain a significant amount of components that are either beneficial or detrimental to cells. Thus, blood exosomes may contribute to As. The aim of this study was to investigate the contribution of exosome proteins to As. Methods Fifty-six subjects were recruited and divided into two comparison pairs:healthy subjects vs. As patients, and hypertension vs. hypertension＋As patients. Serum exosomes were decoded by protein mass spectrometry. Protein profile and function were analyzed by gene ontology (GO).A structure hierarchy tree was constructed to illustrate the proteins associated with GO terms, and protein-protein interaction analysis was performed to indicate the proteins involved in As. Results Five differentiated child terms appeared in both comparisons under the biological process GO terms of “response to stimulus” and “immune system process”. They are “positive regulation of innate immune response”, “immune response-activating signal transduction”, “activation of innate immune response”, “innate immune response-activating signal transduction” and “innate immune response activating cell surface receptor signaling pathway”. Two differentiated child terms emerged in both comparisons in the molecular function category of “binding”:“antigen binding” and “enzyme binding”. In addition, three differentiated proteins, PSMA6, PSMA7 and annexin A2, appeared in both comparisons. Conclusions The innate immune system contributes to AS development. PSMA6, PSMA7 and annexin A2 may be new target proteins for As prevention and treatment.