OBJECTIVE Soluble forms of adhesion molecules (sAM) can block cellular interactions and potentially prevent the adhesion of mononuclear cells to inflammatory tissue. We therefore wondered whether levels of a soluble form of the CD2-ligand CD58 (sCD58) are decreased in patients with different types of joint disease. METHODS SCD58 concentrations were measured by an enzyme-linked immunosorbent assay (ELISA) of sera from 60 patients with rheumatoid arthritis (RA), 13 patients with osteoarthritis (OA), 16 patients with psoriatic arthropathy (PsA), 15 patients with spondylarthropathy (SpA), and 61 age-matched normal controls (NC). SCD58 was also determined in synovial fluid samples (SF) from 42 patients with RA, 12 with PsA, and 12 with SpA. Concentrations of sCD58 were correlated with clinical and laboratory measures of disease activity. Binding of biotinylated human albumin to recombinant CD58 or casein was assessed by a modified ELISA: RESULTS SCD58 levels were significantly reduced in sera from RA patients compared to NC (p < 0.0001), OA (p = 0.019), and SpA (p < 0.0001). Normal concentrations were found in sera from patients with OA, PsA, or SpA. SF sCD58 concentrations were generally lower than serum concentrations (between 18 and 28%). RA SF had significantly lower sCD58 levels than SpA SF (p = 0.01). Reduction of serum sCD58 levels correlated significantly with the ESR (r = 0.56; p < 0.0001), CRP (r = 0.4; p = 0.003), and TJS (r = 0.47; p = 0.0001). In addition, sCD58 serum levels correlated significantly with the reticulocyte count (r = 0.47; p = 0.02) and serum albumin (r = 0.42; p = 0.002). Accordingly, biotinylated human albumin bound to recombinant CD58 in a dose dependent fashion, but not to casein. CONCLUSIONS This study indicates that serum and SF sCD58 levels in patients with RA are reduced compared to the levels in normal controls and patients with OA or SpA. Decreased albumin concentrations due to systemic inflammation may lead to reduced sCD58 levels. Since sCD58 may normally mediate de-adhesion, such a reduction could result in increased T cell adhesiveness.