CTLA-4 is a regulator of co-stimulation and inhibits the activation of T cells through interfering with the interaction of CD80/86 on antigen presenting cells with CD28 on T cells. CTLA-4 binds to the surface of antigen presenting cells, such as dendritic cells and monocytes through CD80/86. Monocytes can differentiate in osteoclasts, the primary bone resorbing cells. Herein, we investigated whether binding of CTLA4 affects the differentiation of monocytes into osteoclasts in vitro and vivo. We show that CTLA-4 dose dependently inhibits RANKL- as well as TNF- mediated osteoclastogenesis in vitro without presence of T cells. Furthermore, CTLA-4 was effective to inhibit TNF-induced osteoclast formation in a non-T cell dependent TNF-induced model of arthritis as well as the formation of inflammatory bone erosion in vivo. These data suggest that CTLA-4 is an anti-osteoclastogenic molecule, which directly binds osteoclast precursor cells and inhibits their differentiation. These findings are an attractive explanation for the anti-erosive effect of abatacept, a CTLA-4-Ig fusion protein used for the treatment of RA.