OBJECTIVE We sought to assess whether circulating levels of intercellular adhesion molecule 1 (ICAM-1) in patients with rheumatoid arthritis (RA) are elevated and correlate with clinical measures of disease activity and whether this ICAM-1 originates from the synovium. METHODS Circulating ICAM-1 (cICAM-1) levels were determined by sandwich enzyme-linked immunosorbent assay of serum from 61 RA, 18 osteoarthritis (OA), and 11 inflammatory arthritis (IA) patients. In addition, paired serum and synovial fluid samples were collected from 17 RA, 9 OA, and 4 IA patients. The stability of cICAM-1 was assessed by overnight incubation at 37 degrees C. Finally, the potential degradative effects of synovial fluid proteases were assessed by incubation of recombinant soluble ICAM-1 with patient synovial fluid. RESULTS RA sera contained significantly greater (P < 0.001) levels of cICAM-1 compared with RA synovial fluid and compared with sera or synovial fluid from the OA and IA patients. Circulating ICAM-1 levels were unaffected by overnight incubation at 37 degrees C and were unaffected by exposure to RA, OA, or IA synovial fluid. Serum levels of cICAM-1 demonstrated a weak, but significant (P < 0.05) correlation with the joint score and erythrocyte sedimentation rate in 25 RA patients treated with nonsteroidal antiinflammatory drugs. CONCLUSIONS The greatest elevations of cICAM-1 were seen in RA patient sera. In both RA and OA, synovial fluid cICAM-1 levels were consistently lower than serum levels, suggesting that cICAM-1 did not originate in the synovium. Because the production of cICAM-1 can be increased by cytokines (e.g., interleukin-1, tumor necrosis factor alpha), elevated levels of circulating ICAM-1 in RA may be reflective of systemic exposure to elevated cytokine levels.