Objective: The aim of this study was to investigate the effects of hydrogen-rich saline on osteoarthritis in rabbit model.Materials and Methods: Fifty rabbits were randomly divided into five groups: control group, model group, hydrogen-rich saline (H2) group, sodium hyaluronate (SH) group and hydrogen-rich saline and sodium hyaluronate compound (H2-SH) group.All rabbits were induced to knee osteoarthritis by injecting papain into the two knees joint except control group.Fourteen days after, intra-articular injections, injected with H2, SH and H2-SH, were performed on osteoarthritic rabbits three times a week for six weeks, and the control group was given no intra-articular injection.Histological examinations of the cartilage and synovium were performed at both three weeks and six weeks, in addition, oxidative stress in serum and synovial joint fluid were evaluated by measuring malondialdehyde (MDA) contents and superoxide dismutase (SOD) activities, inflammation was also evaluated by measuring pro-inflammatory cytokines levels, including interleukin-1 beta (IL-1β3) and tumor necrosis factor alpha (TNF-α).Result: Osteoarthritic rabbits had uneven articular surface with irregular fibrous tissue and even sometime erosion, with concomitant showing hyperemia and swelling in synovium, as compared with the control group.Microscopic histological evaluations showed that H2 group exhibited less damage in cartilage and synovium as compared with the model group.H2 treatment decreased pro-inflammatory cytokines levels, MDA and increased SOD activities.Conclusion: Intra-articular injection of hydrogen-rich saline can delay the progression of cartilage and synovium damage.