Idiopathic CD4 lymphocytopenia (ICL) is a clinically heterogeneous immunodeficiency disorder defined by low numbers of circulating CD4+ T cells and increased susceptibility to opportunistic infections. CD8+ T cells, NK, and/or B cells may also be deficient in some patients. To delineate possible pathogenic cellular mechanisms in ICL, we compared immune system development and function in NOD-RAGKO-γcKO (NRG) mice transplanted with hematopoietic stem cells from patients with ICL or healthy controls. CD34+ hematopoietic stem cells from healthy controls and patients with ICL reconstituted NRG mice equally well. In contrast, PBMC transfers into NRG mice identified 2 ICL engraftment phenotypes, reconstituting and nonreconstituting (NR), based on the absence or presence of donor lymphopenia. For patients in the NR group, the distribution of lymphocyte subsets was similar in the peripheral blood of both the patient and the corresponding humanized mice. The NR-ICL group could be further divided into individuals whose CD3+ T cells had defects in proliferation or survival. Thus, ICL cellular pathogenesis might be classified by humanized mouse models into 3 distinct subtypes:(a) T cell extrinsic,(b) T cell intrinsic affecting proliferation, and (c) T cell intrinsic affecting survival. Humanized mouse models of ICL help to delineate etiology and ultimately to guide development of individualized therapeutic strategies.