A severe CD4 T-cell depletion predisposes humans to opportunistic infections. In recent years, reports of cases of opportunistic infections caused by CD4 T-cell depletion without HIV infection have been accumulating. Such cases, termed idiopathic CD4 T lymphocytopenia (ICL), are very rare. The epidemiologic data do not suggest that the condition is caused by a transmissible agent. Unlike HIV infection, the decrease in the CD4 cell counts of patients with ICL is often slow. The clinical spectrum of ICL ranges from an asymptomatic laboratory abnormality to life-threatening opportunistic infections. However, the pathogens, clinical significance and treatment of ICL patients still await systematic research. This review summarizes the current knowledge of the poorly understood syndrome of idiopathic CD4 lymphocytopenia, providing key insights into the pathogenesis and immunologic characteristics, and suggesting approaches to enhance CD4 T-cell counts.