Soluble adhesion molecules are detectable at low levels in healthy people but are increased in various disorders. However, their physiological role is unknown. Circulating intercellular adhesion molecule-1 (cICAM-1) may modulate inflammation or arise as a consequence of inflammation. We have described elevated concentrations of cICAM-1 in subjects at risk of developing insulin-dependent diabetes mellitus (IDDM), compared with recent-onset IDDM patients and healthy controls. Here we tested the ability of a monomeric soluble recombinant form of ICAM-1 (rICAM-1), to prevent the proliferation of T cells to islet-cell and other antigens. We also tested the ability of two multivalent ICAM-1-immunoglobulin (ICAM-1-Ig) fusion proteins to stop proliferation of T cells in vitro. Autoreactive T-cell proliferation was suppressed by monoclonal antibodies directed against ICAM-1 or lymphocyte-function antigen-1 (LFA-1). Furthermore, 100 mumol rICAM-1 blocked T-cell proliferation in response to an islet-cell autoantigen, and multivalent ICAM-1-Ig fusion proteins were approximately 1,000-fold more effective. The usual interleukin-2-induced proliferation of T cells was unaffected by ICAM or ICAM-Ig. In addition, rICAM-1 blocked primary T-cell responses from peripheral blood mononuclear cells of newly diagnosed IDDM patients in concentrations similar to elevated cICAM-1 concentrations in individuals at risk for the disease. Thus, naturally circulating ICAM-1 may downregulate inflammation in subjects at risk of developing IDDM. Ig-ICAM-1 fusion proteins may thus provide novel means to intervene in the pathogenesis of autoimmune diseases.