AbstractOsteopontin (OPN) and CD44 have been implicated in the development of autoimmune diseases, including arthritis and multiple sclerosis, as well as chronic inflammatory diseases, such as atherosclerosis and colitis. To investigate their roles in autoimmune myocarditis induced by immunization with heart alpha‐myosin (MyHC‐α), a mouse model of human cardiomyopathy, we analyzed mice lacking OPN or CD44v6/v7, a CD44 isoform that binds OPN. Both, OPN–/– and CD44v6/v7–/– mice developed myocarditis with the same prevalence and severity as BALB/c wild‐type controls. Furthermore, treatment of BALB/c mice with a pan‐neutralizing anti‐CD44 antibody did not affect the disease outcome. Consistently, expansion of MyHC‐α‐specific autoimmune CD4+ T cells and MyHC‐α autoantibody responses from either CD44v6/v7–/– mice or OPN–/– mice was indistinguishable from their wild‐type controls. Thus, OPN and CD44v6/v7 are merely spectators rather than protagonists in autoimmune myocarditis.