Atherosclerosis (AS) is characterized by chronic inflammation, which is a significant pathogenic factor of cardiovascular diseases (CVDs). Alleviating endothelial dysfunction and monocyte adhesion are effective ways to halt the development of AS. Membrane Spanning 4-Domains A6A (MS4A6A) is associated with inflammation and primarily regulates immunity and cell signaling. These processes are closely related to the occurrence of AS. However, the specific mechanism remains unclear. In this study, bioinformatics analysis revealed that MS4A6A expression was elevated in human atherosclerotic plaques. Western blot, enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence analyses confirmed that MS4A6A expression correlated with the severity of AS and was significantly expressed in endothelial cells. We determined that MS4A6A was upregulated in atherosclerotic lesions of high-cholesterol diet (HFD) ApoE