Macrophages present in the synovium and synovial fluid of patients with rheumatoid arthritis (RA) express large amounts of HLA-DR molecules on their surface, despite low levels of gamma-interferon (gamma-IFN) in the joint. To determine whether this apparent paradox is the result of increased sensitivity to gamma-IFN in RA, we compared concentrations of gamma-IFN that induced HLA-DR and DQ on peripheral blood monocytes of RA patients and normal donors, using fluorescence-activated cell sorter analysis. Among normal donors, highly variable sensitivity to gamma-IFN was observed. Higher amounts of gamma-IFN were required to induce class II major histocompatibility complex molecules on RA monocytes versus normal monocytes. The maximum amount of HLA-DR that could be induced on RA and normal monocytes was similar; however, peak levels of HLA-DQ were significantly less in RA. Monocytes from patients with other forms of chronic inflammatory arthritis had intermediate HLA-DQ expression after gamma-IFN treatment. These data suggest that an increased sensitivity to gamma-IFN in RA does not account for the high level of HLA-DR expression in the joint. Also, a defect in HLA-DQ and HLA-DR induction by gamma-IFN was observed.