Studies of FcγRII−/− mice identified the inhibitory function of this receptor in joint inflammation and cartilage destruction induced with immune complexes (ICs). To extend our insight in the role of FcγRII in arthritis, we explored the role of FcγRII in the absence of activating receptors I and III using FcγRI/III−/− as well as FcγRI/II/III−/− mice. When antigen-induced arthritis (AIA) was elicited, which is a mixture of T cell and IC-driven inflammation, arthritis was almost absent at day 7 in FcγRI/III−/− mice. Remarkably, in FcγRI/II/III−/− mice, this model induced a tremendously increased arthritis as compared to wild-type controls. This implies that FcγRII regulates joint inflammation also in the absence of activating FcγRI and III. To confirm the IC specificity of this finding, similar studies were done with ICs or zymosan as arthritogenic stimuli. Strongly elevated inflammation was found in FcγRI/II/III−/− mice with IC but not with zymosan. Clearance studies identified accumulation of IgG in the knee joint in the absence of FcγRII. Moreover, macrophages expressing only FcγRII showed prominent endocytosis of preformed soluble ICs not different from controls. In total absence of FcγR (FcγRI/II/III−/−), macrophages completely failed to endocytose ICs. Although joint inflammation was much higher in AIA arthritic knee joints of FcγRI/II/III−/− and the inflammatory cells still expressed an inflammatory phenotype, severe cartilage destruction (MMP-mediated neoepitopes in the matrix and chondrocyte death) was completely prevented in contrast to the marked destruction which was observed in the wild-type. Our study indicates that FcγRII reduces joint inflammation in the absence of activating FcγR by promoting endocytosis and clearance of ICs from the joint. Infiltrating cells, which fail to express activating FcγR although they still become stimulated are no longer capable of inducing severe cartilage destruction.