—To determine whether T cells and B cells influence lipid metabolism and atherosclerosis, we crossed apolipoprotein E–deficient (apoE°) mice with recombination activating gene 2–deficient (RAG2°) mice. Total plasma cholesterol levels were ≈20% higher in male apoE° mice compared with the apoE°RAG2° mice at 8 weeks of age, and plasma triglyceride levels were 2.5-fold higher in the apoE° mice even when plasma cholesterol levels were similar. Male mice with plasma cholesterol levels between 400 and 600 mg/dL at 8 weeks of age were euthanized at 27 and 40 weeks of age. The aortic root lesion area in the apoE°RAG2° mice, compared with that in the immune-competent apoE° mice, was 81% and 57% smaller at 27 and 40 weeks of age, respectively. In contrast, there was no difference in the size of the brachiocephalic trunk lesions. Similar results were obtained with mice euthanized at 40 weeks of age that had 8-week cholesterol levels between 300 and 399 mg/dL. In apoE°RAG2° mice, aortic root atherosclerosis was more profoundly suppressed at lower cholesterol levels. Thus, T and B cells and their products differentially influence the development of atherosclerosis at different sites. We also demonstrate a profound effect of the immune system on plasma lipid homeostasis.