Soluble histocompatibility antigens of the class II region have been detected in synovial fluids obtained from patients with rheumatoid arthritis. A capture immunoassay involving two monoclonal antibodies was used; interference by rheumatoid factor, which is a feature of such assays, was overcome by mild pretreatment of fluids with 2-mercaptoethanol. No HLA class II antigen could be detected in matched sera from patients, even when levels were high in synovial fluids. Released HLA-class II material was of high molecular weight (greater than 1000 kD) and was linked to HLA-class I antigen. However, no significant amounts of other common cell surface antigens were detected in the complex, suggesting a preferential release of MHC antigens from cells of the inflamed synovium. Attempts to induce production of similar material from a cell line which expresses HLA class II strongly at the cell surface, by stressing the cells in various ways did not succeed, indicating that release is an active process.