Binding of Ag-Ab immune complexes to cellular FcγR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcγR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcγRIA, FcγRIIA, and FcγRIIIA were prepared. Binding of rh-FcγRIA to IgG was of high affinity (K D= 1.7× 10− 10 M), whereas rh-FcγRIIA and rh-FcγRIIIA bound with low affinity (K D= 0.6–1.9× 10− 6 M). All rh-FcγR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF-α by cultured mast cells. Local or systemic delivery only of rh-FcγRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125 I-labeled rh-FcγRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with at 1/2 γ of∼ 130 h. The highest percentage of injected radioactivity accumulated in blood∼ liver∼ carcass> kidney. sc dosing of rh-FcγRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcγRIA is an effective inhibitor of type III hypersensitivity.