The response of macrophages to stimulation by interferon-gamma (IFN-gamma) in vitro is characterized by an increase in the cell surface expression of MHC class II HLA-DR antigen (HLA-DR) and the high-affinity Fc-receptor for immunoglobulin G (FcRI) while the expression of the C3b-receptor (CR1) is reduced. Based on these observations, we have examined further the possibility that IFN-gamma may modulate the activation of mononuclear phagocytes (Mph) in patients with rheumatoid arthritis (RA). As reported by others, we found low levels of IFN-gamma in the synovial fluid of these patients (less than 0.3 IU/ml using radioimmunoassay). As an alternative means of establishing whether Mph are influenced by levels of IFN-gamma too low to measure directly, we have quantified the expression of membrane associated HLA-DR, FcRI and CR1 on cell populations isolated from synovial fluid and peripheral blood. The expression of these molecules by Mph is known to be influenced by IFN-gamma. We found that Mph isolated from the synovial fluid of patients with RA showed a significantly increased HLA-DR expression. Significantly less CR1 was associated with the synovial fluid Mph than with peripheral blood monocytes. However the expression of the FcRI by the synovial fluid Mph and peripheral blood monocyte populations was similar. The quantitative changes in HLA-DR and CR1 expression by synovial fluid Mph (but not those of FcRI) were consistent with those seen following IFN-gamma activation of monocytes in vitro. While these results indicate that IFN-gamma may have a role in activating the Mph present in synovial fluid, the apparent independent regulation of FcRI observed suggests other mediators may also be involved.