Binding of immune complexes to cellular FcγRs can promote cell activation and inflammation. In previous studies, a recombinant human (rh) soluble FcγR, rh-FcγRIA (CD64A), was shown to block inflammation in passive transfer models of immune complex-mediated disease. To assess whether rh-FcγRIA could block inflammation in a T cell-and B cell-dependent model of immune complex-mediated disease, the efficacy of rh-FcγRIA in collagen-induced arthritis was evaluated. Mice with established arthritis were treated with a single sc injection of rh-FcγRIA (0.2–2.0 mg/dose) given every other day for 11 days. Relative to mice injected with vehicle alone, mice treated with rh-FcγRIA exhibited lower serum concentrations of IL-6, anti-type II collagen Abs, and total IgG2a. These changes were correlated with lower levels of paw swelling and joint damage in the rh-FcγRIA-treated mice and occurred in the presence of a significant murine Ab response to rh-FcγRIA. Comparison of the serum rh-FcγRIA concentration vs time profiles for rh-FcγRIA administered at two dose levels by iv and sc injection revealed that the bioavailabilty of sc administered rh-FcγRIA was 27–37%. Taken together, these data show that rh-FcγRIA is an effective inhibitor of inflammation in a model of established arthritis in mice.