There are different causes of CD4 lymphocytopenia: neoplastic pathology, immunosuppressive therapy or other iatrogenic forms. In addition to these causes, an important role is certainly played by HIV infection which, at the AIDS stage, constantly accompanies progressive CD4 lymphocytopenia, with or without affecting the other lymphocyte components. CD4 lymphocyte deficits not correlated to HIV infection are relatively rare and are not always accompanied by progressive clinical manifestations of immunodeficiency. In the recent past an idiopathic form of CD4 lymphocytopenia (ICL) was recognised whose diagnostic criteria were defined by the Center for Disease Control (CDC) in Atlanta. Cases of ICL association with hepatitis C virus infection have been reported and anomalies partially shared by subjects suffering from common variable hypogammaglobulinemia (CVH) have been reported in some ICL carriers. The CD4 deficit in these patients is not associated with other cellular and/or humoral immunological anomalies and the clinical manifestations, essentially of scant importance, have not shown signs of progression towards severe immunodeficiency syndromes. The authors report 4 subjects with major CD4 deficit whose clinical characteristics do not match idiopathic lymphocytopenia and specific serological tests have excluded HIV infection. No known causes of CD4 lymphocytopenia have been found in these patients and they do not present major signs of clinical damage.