It has been demonstrated that T cells bearing HLA-DR antigens on their surface are actively involved in an immune response. In diseases of disordered immunoregulation, including rheumatoid arthritis (RA), there are elevated numbers of circulating HLA-DR+ T cells. In this study, we examined the cellular physiology of these T cells in RA patients. Using tritiated thymidine incorporation, we found that, in most patients, HLA-DR+ cells do not account for a significant amount of spontaneous proliferation found in peripheral blood T cells. RNA hybridization studies, using a cloned HLA-DR alpha chain gene probe, indicate that the T cells actively synthesize HLA-DR antigens rather than passively adsorbing them. The cell surface phenotype of the HLA-DR+ T cells was analyzed using double immunofluorescence and a variety of monoclonal antibodies. The expression of T cell differentiation antigens T4, T6, T8, and T10 varied markedly from patient to patient. In some patients, a significant number of cells expressed both T4 and T8 antigens. Most HLA-DR+ cells also express antigens defined by the following antibodies: anti-Tac (the interleukin-2 receptor), J2 (a glycoprotein found on T cell blasts), and ILR-1 (a class II major histocompatibility complex antigen). Activated T cells bearing HLA-DR antigens may play a role in the development of RA. Our data demonstrate that although these cells are not lymphoblasts, they possess a distinct cell surface phenotype.