Recent studies have demonstrated the importance of lymphocytes, especially CD4⁺ T cells, in early lesions of atherosclerosis in hypercholesterolemic mice. However, the role of other T cell subpopulations, like CD8⁺ T cells or TCRγδ T lymphocytes, is not yet clear. We have therefore generated apolipoprotein E-deficient mice genetically deficient in specific T lymphocyte subpopulations and measured atherosclerotic lesions in the aortic sinus and en face whole aorta preparation at 18 weeks and at 1 year of age. Whereas TCRγδ⁺ T lymphocytes appeared to play a modest role, TCRαβ⁺ T lymphocytes played a major role as their deficiency significantly prevented early and late atherosclerosis at all arterial sites. However, neither CD4⁺ nor CD8⁺ T cells induced any significant decrease of the lesions at the aortic sinus, suggesting that compensatory proatherogenic mechanisms are operating at this site. Interestingly, the absence of CD4⁺ T cells led to a dramatic increase in early lesion abundance at the level of the descending thoracic and abdominal aorta, which was still obvious at 1 year. In conclusion, whereas the TCRαβ⁺ lymphocyte subset in its whole contribute to aggravate both early and late atherosclerosis, the CD4⁺ T subpopulation appears to be critically protective at the level of the lower part of the aorta.