Background and aim: Adaptive immune cells are involved in the development of atherosclerosis. Here we provide the immunemetabolic profile of an atheroprone immunodeficient mouse humanized with hCD34+ cells. Methods: LDLR-KO mice were crossed with the immunodeficient Rag2-KO/IL2rg-KO/CD47-KO (TKO, IMSR_JAX:025730) mouse model to generate an immunocompromised dyslipidemic mouse (TKO-LDLR KO mice). These mice present an intact innate immune system but lack B and T lymphocytes as well as NK cells. New born mice (within three days) were sub lethally irradiated (200 cGy) and received 2 x 10^5 hCD34+ cells. Results: when fed a cholesterol rich diet, non humanized TKO-LDLR KO present monocytosis with increased levels of Ly6Chi monocytes compared to TKO-LDLR KO at standard diet. Moreover, they develop marked dyslipidemia (plasma chol levels >1200mg/dL), liver steatosis and moderate atherosclerosis at the aortic arch. The engraftment of human leukocytes (hCD45+) in the humanized group was evaluated after two months by flow cytometry analysis. Within the totality of circulating CD45+ cells, 10 to 30% were hCD45+, mainly B and T cells. Of note the presence of human lymphocytes was associated with a dramatic worsening of atherosclerosis as compared to non-humanized TKO-LDLR KO mice which was independent of plasma cholesterol levels which remained ex. Conclusion: Adoptive transfer of human CD34+ cells in dyslipidemic Rag2-KO/IL2rg-KO/CD47-KO immunocompromised mice promotes atherosclerosis independently of hypercholesterolemia, by affecting the maturation and distribution of the different B and T lymphocyte subsets.