BACKGROUND AND PURPOSE: Annexin A1 (AnxA1) is an endogenous anti-inflammatory molecule that binds to the formyl-peptide receptor 2 (FPR2). However, the potential for therapeutic FPR ligands to modify immune-mediated disease has been little explored. We investigated the effects of a synthetic FPR ligand on joint disease in the K/BxN model of RA and RA fibroblast-like synoviocytes (FLS). EXPERIMENTAL APPROACH: Arthritis was induced by injection of K/BxN serum at day 0 and 2 in wild-type or AnxA1-/- mice, and clinical and histopathologic manifestations measured. WT mice were treated with the FPR agonist compound 43 (Cpd43) (6 or 30 mg/kg). Effects of AnxA1 and Cpd43 were also assessed in RANKL- induced osteoclastogenesis in RAW 264.7 cells, and in human RA FLS and macrophages. KEY RESULTS: Treatment with Cpd43 before or after the onset of arthritis significantly reduced clinical disease severity and attenuated synovial TNF-alpha and osteoclast-associated gene expression. Conversely, deficiency of AnxA1 in mice exacerbated arthritis severity in the K/BxN model. In vitro, Cpd43 suppressed osteoclastogenesis and NFAT activity elicited by RANKL, and inhibited IL-6 secretion by mouse macrophages. In human RA joint-derived FLS and monocyte-derived macrophages, Cpd43 treatment also inhibited IL-6 release, while blocking FPR2 or silencing AnxA1 had the reverse effect. CONCLUSIONS AND IMPLICATIONS: These data demonstrate that the FPR agonist Cpd43 reduces osteoclastogenesis and inflammation in a mouse model of RA and exhibited anti-inflammatory effects in relevant human cells. These data suggest that FPR ligands may represent novel therapeutic agents with which to ameliorate inflammation and bone damage in RA.