BACKGROUND: Atherosclerosis, a leading cause of cardiovascular disease, is characterized by intricate interactions among lipid metabolism, inflammation, and immune response. Investigating immune-related genetic factors and immune cell infiltration in atherosclerotic tissues may provide insights into potential therapeutic targets. METHODS: We analyzed transcriptomic data from atherosclerotic and normal tissues to identify differentially expressed genes (DEGs). Functional enrichment was performed using KEGG and GO pathway analyses, and immune-related DEGs were identified by intersecting DEGs with immune-related gene sets. Mendelian randomization (MR) was utilized to examine the causal relationship between immune-related DEGs and atherosclerosis. Immune cell infiltration was evaluated using Cibersort, MCP-counter, and xCell. Again, MR was performed to assess the causal effects of 731 immunophenotypes on atherosclerosis. RESULTS: A total of 428 DEGs were identified between atherosclerotic and normal tissues, of which 112 were immune-related. Immune cell infiltration analysis highlighted significant differences, particularly in CD8 T cells and B cells. MR analysis demonstrated a significant causal relationship between HLA-DR on dendritic cells (OR [95%CI] =1.04[1.02-1.06], p = 1.03e-5) and coronary atherosclerosis. Furthermore, HLA-DR on myeloid dendritic cells (OR [95%CI] =1.12[1.07-1.17], p = 3.13e-06) and CD8 on CD8+ T cells (OR [95%CI] =1.12[1.05-1.18], p = 2.00e-04) were causally linked to atherosclerosis (excluding cerebral, coronary, and PAD). CONCLUSION: Our findings highlight the crucial involvement of immune-related DEGs and specific immune cell types in the development of atherosclerosis. These results suggest that targeting immune pathways, particularly HLA DR on dendritic cells and CD8 on CD8+ T cells, may offer promising therapeutic strategies for atherosclerosis.