Because of their increased malignancies, autoimmune diseases, and infections, patients with Down syndrome (DS) show features of immunodeficiency. The DS thymus and T lymphocyte subsets have indeed proven to be different, and this has been interpreted as precocious aging. Our study on T lymphocyte subpopulations in DS shows that the normal expansion of naive helper (CD4CD45RA) and cytotoxic (CD8CD45RACD27) T lymphocytes is lacking in the first years of life; this is more logically explainable with an intrinsic T lymphocyte defect. Furthermore, memory cell numbers are not different from age-matched controls (AMC), which does not support the hypothesis of precocious aging. Although the absolute numbers of T lymphocyte subpopulations approach AMC levels toward adulthood, the persistent clinical problems suggest that these cells may not function optimally. However, the clinical picture does not fit severe T lymphocyte deficiency. The latter concept is also supported by our finding that cytomegalovirus (CMV)-seropositive DS children show similar numbers of terminally differentiated cytotoxic T lymphocytes when compared with healthy children, not increased numbers as are seen in immunocompromised hosts.