Phenotype and proliferative ability of peripheral blood lymphocytes from 15 noninstitutionalized children affected with Down Syndrome (DS), in apparently good health, were studied and compared with those of 16 healthy control children of the same age. A complex derangement of all the major peripheral blood cell subsets, i.e., B cells, T cells, and natural killer (NK) cells, was present in DS children. A significant decrease of the absolute number of circulating lymphocytes, a marked and significant decrease of B lymphocyte absolute number and percentage, and dramatic modifications of the T-cell subsets were observed. The absolute number of CD4+ cells was significantly decreased, whereas CD8+ cells increased significantly in percentage but not in absolute number. A derangement of cells bearing markers associated with NK activity, such as CD57, CD16, and CD56, was observed. Among the most important alterations, the presence of a high number of CD57+, CD16- cells, of CD57+, CD8+ lymphocytes, and of CD3+, CD56+ lymphocytes was seen. Many of these alterations are similar to those characteristic of chromosomally normal subjects of advanced age. The hypothesis that the reduced thymic endocrine activity and the zinc deficiency characteristic of DS are responsible for the derangement of T and NK subsets is discussed.