Although osteoarthritis (OA) is the most prevalent aging-related joint disease, the understanding of mechanisms of OA pathogenesis remains limited. Key features include the progressive degradation of articular cartilage, synovial hyperplasia, and angiogenesis in joint tissues. CD9, a member of the tetraspanin family, is localized in the cell membranes and partly in the endosomes of all mammalian cell types. CD9 is associated with inflammation and angiogenesis through cell adhesion, migration, and signal transduction. This study examined the role of CD9 in OA development in three different mouse models: an aging model, a surgical model and antigen-induced arthritis (AIA) model, using CD9 deficient mice. Our study showed that CD9 deficiency reduced the severity of hallmarks of OA including cartilage degradation and soft tissue inflammation in aged mice. In the AIA model, cartilage damage and inflammation were also reduced in CD9-/- mice. This was in contrast to the surgical OA model where disease severity was similar in wild-type and CD9-/- mice. Col2a1 and Aggrecan expression was increased in chondrocytes of CD9-/- mice compared with those of wild-type mice. Our results indicate that the suppression of cartilage degradation in CD9-/- could be in part related to an increase in the expression of the two main cartilage extracellular matrix proteins aggrecan and type II collagen.