Sjögren's syndrome (SS) is an autoimmune disease that is characterized by dryness of the mouth and eyes. The loss of salivary and lacrimal gland function is accompanied by lymphocytic infiltration. Because similar symptoms and glandular pathology are observed in certain persons infected with human immunodeficiency virus (HIV), a search was initiated for a possible retroviral etiology in this syndrome. To investigate the possibility of an immune response to retroviral antigens or that of detecting retrovirus in primary SS, I performed immunoblotting assay, immunohistochemical assay, polymerase chain reaction (PCR), and reverse transcriptase (RT) activity assay. Sera from 33% of 15 patients with SS, reacted against p24 group specific antigen (gag) of HIV. Labial salivary gland biopsy specimens from 47% of the 15 patients with SS contained an epithelial cytoplasmic protein reactive with a monoclonal antibody to p24 of HIV. I performed PCR to detect HIV and human T lymphotropic virus type I (HTLV-I)genes in salivary gland tissues and peripheral blood mononuclear cells (PBMC) from patients with SS. I also detected Mn2+ dependent, Mg2+ independent RT activity in the salivary gland tissues in 3 of 10 patients with SS. Target genes for HIV and HTLV-I were not found in any of the salivary gland tissues or PBMC from patients with SS. These data suggested the presence of an unknown retrovirus similar to HIV in the salivary gland that may contribute to chronic inflammation in SS.