Objective To investigate the effects of vaccination with AGE-LDL against atherosclerosis in two diabetic mice models and involved mechanism.Methods Female apoE and LDLR deficient mice were fed with high fat and induced to diabetes by intraperitoneal injection of streptozotocin at age of 6 weeks for 7 days, and after two weeks these mice were randomized to receive either PBS, or Alum adjuvant, or combination of Alum adjuvant with AGE-LDL injection subcutaneous once two weeks for four times.Ten weeks later all mice were sacrificed.Concentrations of serum total cholesterol, LDL, HDL, and triglyceride were measured.Atherosclerotic lesions were analyzed by staining with Oil red O, MOMA-2 antibody, Masson s trichrome, and alpha-SMC antibody detected by DAB kits.Percentages of Th1, Th2, Treg and T17 cells in spleens were assessed by flow cytometry.Total IgG(IgG1 and IgG2a), IgM, specific IgG and IgM against AGE-LDL, and immune-related cytokines in serum or splenocytes supernatant were also detected with Milliplex assay kits.Results Compared with PBS or Alum adjuvant, combined immunization strategy could significantly decrease atherosclerotic burden, which could increase serum HDL levels, show decreasing trend of H1bAc, induce specific IgG and IgM antibody against AGE-LDL, upregulate Th2, Treg percentage and IL-10 levels, without altering Th1 or Th17 percentages.Conclusion Subcutaneous immunization with combination of AGE-LDL and alum adjuvant could significantly inhibit atherosclerosis progression in diabetic mice with hyperlipidemia, which could be attributed to activation of specific humoral and cell mediated immune response against AGE-LDL and improvement of metabolic control.Such vaccination strategy would provide a novel and promising therapy strategy against atherosclerosis in clinic.