Vascular cell adhesion molecule-1 (VCAM-1, CD106) is important in leukocyte trafficking and its increased expression is associated with a number of chronic inflammatory diseases, including rheumatoid arthritis (RA). A soluble form of VCAM-1 (sVCAM-1) is generated by shedding of the membrane-bound molecule. The concentration of sVCAM-1 is increased in the sera of RA patients, but its pathological role has not been elucidated. The effect of sVCAM-1 relative to protection or aggravation of disease on the development of spontaneous arthritis was examined in an animal model of RA, namely MRL-Fas(lpr) mice (which display a disease resembling human RA), by generation of sVCAM-1 transgenic MRL-Fas(lpr) mice. Transgenic MRL-Fas(lpr) mice that expressed sVCAM-1 had higher incidence and increased severity of arthritis associated with higher levels of serum IgG rheumatoid factor compared with non-transgenic MRL-Fas(lpr) mice. These results suggest that sVCAM-1 plays an arthritogenic role in the development of inflammatory arthritis in MRL-Fas(lpr) mice and may present an important target for therapeutic strategy of RA.