Objective. Although several ginsenosides have been reported to have anti-arthritic activity, few in vivo studies of the anti-arthritic effects of compound K (CK), a major metabolite of ginsenosides, have been conducted. Therefore, we investigated the preventative and therapeutic effects of CK on collagen-induced arthritis (CIA). Methods. CK was administered to CIA mice preventively and therapeutically and post-treatment bone microarchitectural characteristics, histopathological changes, and serum levels of anti-collagen antibodies, tumor necrosis factor-α, and interleukin (IL)-17 were investigated. We also examined cytokine production by type II collagen (CII)-stimulated splenocytes and mRNA expression of matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinase (TIMP)-1, receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG) in the joint tissues. Results. CK reduced the severity of CIA preventively and therapeutically (all p<0.05). Additionally, CK dose-dependently decreased histopathological signs of arthritis and improved microarchitectural characteristics (all p <0.05) at 10 to 20 mg/kg/d in CIA mice. CK treatment significantly decreased the serum levels of anti-CII immunoglobulin G (p<0.01) and the secretion of interferon-γ and IL-2 from stimulated splenocytes (all p<0.05). Furthermore, MMP-3/TIMP-1 and RANKL/OPG ratios were suppressed in CK treated mice (all p<0.01). Conclusion. CK attenuated CIA via suppression of the humoral immune response and modulation of joint-destructive mediators. These results suggest that CK has therapeutic potential in rheumatoid arthritis (J Rheum Dis 2015;22:154-166)