Idiopathic CD4+ T lymphocytopenia (ICL) is an immunodeficiency syndrome characterized by severe depletion of CD4+ T lymphocytes, but in which human immunodeficiency virus cannot be detected. Peripheral blood mononuclear cells (BPMCs) from an ICL patient were cocultured with HUT78 T-lymphoblastoid cells, and an acute cytopathic effect and formation of multinucleated cells were observed. A human intracisternal A-type retroviral particle designated HIAP-II was detected in cells surviving the acute cytopathic effect. Eight of 13 ICL patients in a blinded screen of a serological panel provided by the National Centers for Disease Control and Prevention (CDC) had serum antibodies that specifically reacted with HIAP-II associated proteins by Western immunoblotting. None of 19 control sera in the panel that were unreactive with HIV Gag proteins produced a positive result on HIAP-II immunoblots. Comparable results were obtained in a blinded screen of a second CDC serological panel. Sera from 8 of 14 ICL patients in the second serological panel were positive for antinuclear autoantibodies (ANAs) commonly observed in patients with systemic autoimmune diseases. These results suggest the possible involvement of an A-type retrovirus or autoimmunity in development of ICL in a subset of patients.