Using monoclonal antibodies to cell surface antigens, we studied lymphocyte subsets in 15 patients with primary Sjögren's syndrome. The absolute number of OKT8-positive cells (reactive with T suppressor/cytotoxic cells) was significantly decreased in such patients (353±186/mm 3) compared to age-matched controls (631±150/mm 3)(P< 0.001). The number of OKT4-positive cells (reactive with T helper/inducer cells) was comparable in both groups (932±588/mm 3 versus 1.073±290/mm 3). The ratio of OKT4/OKT8-reactive peripheral blood lymphocytes was increased (> 2.4) in 67% of these patients and ranged from 1.0 to 6.4 (normal= 1.8±0.3). OKT4-positive cells were the predominant subset in lip biopsy specimens stained with immunofluorescence or immunoperoxidase techniques; the OKT4/OKT8 ratio exceeded 3.0 in all 5 patients examined. In 1 patient with pseudolymphoma, a lymph node biopsy specimen contained 80% T cells with an OKT4/OKT8 ratio of 3.2. Thus, OKT4-positive cells predominated in the peripheral blood lymphocytes as well as in sites of inflammation in primary Sjögren's syndrome. The decreased number of OKT8-positive cells in primary Sjögren's syndrome was probably not caused by circulating autoantibody, since patients' sera did not react with normal OKT8-positive cells. Functional studies using pokeweed mitogen demonstrated that T helper cell activity for immunoglobulin synthesis was contained in the OKT4-positive subset in both normal and patients' peripheral blood lymphocytes. Removal of OKT8-positive cells by complement-mediated lysis did not lead to increased immunoglobulin synthesis or production of rheumatoid factor. The identification of peripheral blood lymphocyte subsets by use of monoclonal antibodies and the relationship of these subsets to tissue infiltrates and autoantibody production provide further insight into the pathogenesis of primary Sjögren's syndrome.