A number of non-human-immunodeficiency-virus (HIV) type 1 disorders are associated with CD4+ T-cell deficiency and dysfunction. However, the etiopathogenesis of CD4+ T-cell immunodeficiency in these disease states remains unclear. Human intracisternal retroviral (HICRV) particles were detected in a lymphoblastoid cell line exposed to mononuclear cells from a patient with severe CD4+ T-cell deficiency without risk factors for HIV infection. Ultrastructurally, the HICRV is distinct from HIV-1, HIV-2, human T-lymphotropic virus (HTLV) type I, and HTLV-II. Supernatants of activated mononuclear cells showed significant reverse transcriptase activity that was predominantly Mn2+ dependent. The patient's mononuclear cells were negative for HIV-1, HIV-2, HTLV-I, and HTLV-II proviruses as demonstrated by the lack of amplification by PCR. Also, the patient's serum was negative for antibodies to HIV-1, HTLV-I, and HTLV-II and for HIV-1 p24 antigen; however, serum was positive for antibodies against the HICRV as demonstrated by Western blot. Similar HICRV particles were detected in a lymphoblastoid cell line exposed to mononuclear cells from the patient's daughter, who showed CD4+ T-cell dysfunction. The HICRV may be associated with CD4+ T-cell immunodeficiency and dysfunction in patients without risk for HIV-1, HIV-2, HTLV-I, and HTLV-II.