BACKGROUND The human immunodeficiency virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome (AIDS), infects and depletes CD4+ T lymphocytes. Recently, patients have been described with profound CD4+ T-lymphocytopenia but without evident HIV infection, a condition now termed idiopathic CD4+ T-lymphocytopenia, and a national surveillance network has been set up to investigate such cases. METHODS We studied 12 patients with CD4+ T-lymphocytopenia who were referred to us from three U.S. cities. Blood samples were tested for HIV with specific antibody assays, viral cultures, and polymerase-chain-reaction (PCR) techniques. RESULTS The patients (10 men and 2 women) ranged in age from 30 to 69 years. Eight had risk factors for HIV infection. The clinical manifestations were heterogeneous: five patients had opportunistic infections, five had syndromes of unknown cause, and two had no symptoms. Two patients died from acute complications of their immunodeficiency. The patients' lowest CD4+ lymphocyte counts ranged from 3 to 308 per cubic millimeter (mean, 149). Three patients had complete or partial spontaneous reversal of the CD4+ T-lymphocytopenia. Concomitant CD8+ T-lymphocytopenia was noted in three patients, and abnormal immunoglobulin levels were found in five. Multiple virologic studies by serologic testing, culture, and PCR were completely negative for HIV in all patients. CONCLUSIONS Our 12 patients with idiopathic CD4+ T-lymphocytopenia appear to be epidemiologically, clinically, and immunologically heterogeneous. It is unclear whether this syndrome is new, transmissible, or acquired. Many of the clinical and immunologic features are distinct from those found in AIDS, and our extensive virologic studies found no evidence of HIV infection. The cause of this condition remains unknown.