Idiopathic CD4 lymphocytopenia (ICL) is a presumed heterogenous syndrome with key element low CD4 T-cell counts (below 300/mm³) without evidence of HIV infection or other known immunodeficiency. The etiology, pathogenesis, and management of ICL remain poorly understood and inadequately defined. The clinical presentation can range from serious opportunistic infections to incidentally diagnosed asymptomatic individuals. Cryptococcal and non-tuberculous mycobacterial infections and progressive multifocal leukoencephalopathy are the most significant presenting infections, although the spectrum of opportunistic diseases can be similar to that in patients with lymphopenia and HIV infection. Malignancy is common and related to opportunistic pathogens with an oncogenic potential. Autoimmune diseases are also seen in ICL with an increased incidence. The etiology of ICL is unknown. Mechanisms implicated in CD4 reduction may include decreased production, increased destruction, and tissue sequestration. New distinct genetic defects have been identified in certain patients with ICL, supporting the hypothesis of the lack of a common etiology in this syndrome. The management of ICL is focused on the treatment of opportunistic infections, appropriate prophylactic antibiotics, and close monitoring. In selected patients with life-threatening infections or profound immunodeficiency, strategies to increase T-cell counts or enhance immune function could be considered and have included interleukin-2, interferon-gamma, interleukin-7, and hematopoietic stem cell transplantation. The prognosis is influenced by the accompanying opportunistic infections and may be affected by publication bias of severe cases with unfavorable outcomes. As newer laboratory investigation techniques are being developed and targeted experimental treatments become available, our comprehension and prognosis of this rare syndrome could be significantly improved.