Idiopathic CD4 lymphocytopenia (ICL) is a rare disorder of unknown etiology. Diagnostic criteria include a persistent CD4 T-cell lymphopenia with no underlying primary or secondary immune deficiencies and a CD4 T-cell count of 300 cells/mL or 20% total lymphocyte on multiple occasions.To increase awareness of ICL and to provide a review of the clinical characteristics, diagnosis, and management of this disease process. Presently, many of these patients receive prophylactic treatment similar to other T-cell deficient conditions, most notably patients with human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome; however, the same indications may not necessarily apply to this patient population because the T cells are not affected by a virus as in HIV.A literature search of salient articles that describe case reports and case series of ICL and their management were analyzed.A case of ICL with a literature review is presented with emphasis on clinical pearls and pitfalls. The patients with ICL are usually identified with a CD4 count of 200 cells/mL when complications develop. Opportunistic infections are the most common initial manifestations. Current therapies used to increase CD4 levels include interleukin 2, interferon gamma, interleukin 7, and allogeneic hematopoietic stem cell transplantation, with variable results.ICL is a diagnosis of exclusion when there is no identifiable underlying cause for a low CD4 count. Although the nature of the T-cell problem is not the same in ICL and HIV, in the absence of specific guidelines, patients receive the same prophylactic treatment as patients with HIV.