Lymphocytes upon activation release a soluble form of interleukin 2 receptor (IL-2R). Systemic autoimmune disorders are characterized by immune system disregulation associated with cellular activation; therefore we sought to determine the levels of soluble IL-2R molecules in the serum of patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjogren's syndrome (1 degree SS). Utilizing an enzyme immunoassay method we found increased serum levels of soluble IL-2R in 65.4% (34/52) of RA, in 34.9% (15/43) of SLE, and in 25.0% (13/52) of 1 degree SS patients, compared to 4.2% (1/24) of healthy individuals. High serum levels of soluble IL-2R correlated with several indices of disease activity in RA and SLE patients, as well as with disease progression to extraglandular involvement and to pseudolymphoma or lymphoma in patients with 1 degree SS. By gel filtration analysis, the soluble IL-2R circulating in the serum of a RA patient corresponded to a high molecular weight molecule (greater than 90 kDa) compared to the 65-kDa soluble IL-2R molecule released by phytohemagglutinin-stimulated normal peripheral lymphocytes.