Objective: Down syndrome (DS) is associated with an increased frequency of infections, hematologic malignancies, and autoimmune diseases, suggesting that immunodeficiency is an integral part of DS that contributes significantly to the observed increased morbidity and mortality. We determined the absolute counts of the main lymphocyte populations in a large group of DS children to gain further insight into this immunodeficiency. Study design: In a large group of children with DS (n = 96), the absolute numbers of the main lymphocyte subpopulations were determined with 3-color immunophenotyping using the lysed whole-blood method. The results were compared with previously published data in healthy children without DS. Results: In healthy children with DS, the primary expansion of T and B lymphocytes seen in healthy children without DS in the first years of life was severely abrogated. The T-lymphocyte subpopulation counts gradually reached more normal levels with time, whereas the B-lymphocyte population remained severely decreased, with 88%of values falling below the 10th percentile and 61%below the 5th percentile of normal. Conclusions: The diminished expansion of T and B lymphocytes strongly suggests that a disturbance in the adaptive immune system is intrinsically present in DS and is not a reflection of precocious aging. Thymic alterations have been described in DS that could explain the decreased numbers of T lymphocytes, but not the striking B lymphocytopenia, seen in these children. Determining the absolute frequency of the disease main lymphocyte populations in a large group of DS children to gain further insight into this immunodeficiency. Study design: In a large group of children with DS (n = 96), the absolute numbers of the main lymphocyte subpopulations were determined with 3-color immunophenotyping using the lysed whole-blood method. The results were compared with previously published data in healthy children without DS. Results: In healthy children with DS, the primary expansion of T and B lymphocytes seen in healthy children without DS in the first years of life was severely abrogated. The T-lymphocyte subpopulation counts gradually reached more normal levels with time, while the B-lympho cyte population yet severely decreased, with 88% of values ​​falling below the 10th percentile and 61% below the 5th percentile of normal. Conclusions: The diminished expansion of T and B lymphocytes strongly suggests that a disturbance in the adaptive immune system is intrinsically present in DS and is not a reflection of precocious aging. Thymic alterations have been described in DS that could explain the decreased numbers of T lymphocytes, but not the striking B lymphocytopenia, seen in these children.