Background: Osteoprotegerin (OPG) is involved in the pathogenesis of osteoarthritis, but the specific molecular mechanism of its action has not been completely clarified. Thus, the purpose of this study was to investigate the effect of OPG upon the growth of chondrosarcoma cells and further explore its potential mechanism in osteoarthritis pathogenesis. Methods: Human chondrosarcoma cells (SW1353) were treated with different concentrations of OPG. Further, cell proliferation rate was detected by MTT assay and ELISA, and matrix metalloprotease-13 (MMP-13) expression was determined through real-time reverse transcriptase-polymerase chain reaction (real-time RT-PCR) and Western blot. Results: Our results showed that OPG significantly promoted cell proliferation of chondrosarcoma cells in a dose-dependent manner. The expression of both MMP-13 mRNA and protein in the SW1353 cells was inhibited by the treatment with OPG. The downregulation of MMP-13 by OPG was associated with the protective effect of OPG on the proliferation of SW1353 cells, which may contribute to the prevention of osteoarthritis. Conclusions: OPG inhibits MMP-13 expression in chondrosarcoma cells, a mechanism which might contribute to the use of OPG as a new therapeutic agent in the treatment of osteoarthritis.