Rheumatoid arthritis (RA) is an autoimmune disease which may lead to severe disabilities due to structural joint damage and extraarticular manifestations The dendritic cell marker CD83 belongs to the immunoglobulin superfamily and has previously been associated with autoimmune diseases. In RA the levels of soluble CD83 (sCD83) are elevated in synovial fluid, however little is known about CD83 expression and regulation in RA. Therefore, we studied how CD83 is expressed in RA and further evaluated the effect of anti-TNF-α therapy hereon. Early RA patients were randomized to conventional disease modifying anti-rheumatic drugs with or without additional anti-TNF-α therapy. Rheumatoid arthritis patients had increased levels of sCD83 in plasma compared with healthy volunteers. The increase in sCD83 plasma levels were unaffected by anti-TNF-α therapy. In chronic RA patients the levels of sCD83 were higher in synovial fluid than in plasma, and only a limited amount of membrane bound CD83 expression was detected on the surface of cells from peripheral blood and synovial fluid. Finally, confocal microscopy of RA synovial membranes revealed that CD83 was mainly localized intracellularly in a group of cells with diverse morphology including both antigen-presenting cells and non-antigen-presenting cells. Our findings demonstrate that early-stage RA patients have elevated levels of sCD83 in plasma and that anti-TNF-α treatment has no effect on the sCD83 plasma level. This suggest that in RA patients sCD83 regulation is beyond control of TNF-α.