We sought to detect anti-Fc gamma receptor (FcγR) autoantibodies and soluble FcγR in the serum and synovial fluid (SF) from patients with rheumatoid arthritis (RA) and to correlate these serological abnormalities to the polymorphonuclear cell (PMN) activation state. Paired samples of blood and SF were obtained from 33 RA patients as well as blood from 25 normal adults from SF from 20 non-RA patients. Anti-FcγR autoantibodies were assessed by an enzyme-linked immunosorbent assay (ELISA) using recombinant human FcγR as the substrate. Soluble FcγRIII was determined by an ELISA based on the combination of two monoclonal antibodies (MAb). The mean fluorescence intensity (MFI) of complement receptor 1 (CD35) and 3 (CD11b) and FcγRIII (CD16) was evaluated by flow cytometry on the membrane of PMN. IgM anti-FcγRIII activity was present in seven RA sera and five SF, and IgG in eight RA sera and six SF. The average concentration of soluble FcγRIII was 1.80 ± 3.50 μg/ml in RA patients and 0.33 ± 0.06 μg/ml in normal adults (P<0.05). This was elevated in the SF of 15 RA, while normal in that of all the non-RA patients. There was an inverse correlation between the CD16 MFI on the PMN and the serum/SF soluble FcγRIII level, whereas the density of CD35 and CD11b was markedly augmented. Anti-FcγRIII activity exists in RA patients, associated with soluble FcγRIII. PMN activation could be due to these autoantibodies and thereby obviate the clearance of immune complexes.