Autoimmune hemolytic anemia (AHA) is characterized by the production of Coombs' antibodies, which are responsible for the destruction of red blood cells (RBCs). Analysis of both monoclonal anti-RBC autoantibodies derived from autoimmune New Zealand black mice and transgenic mice expressing a pathogenic IgM anti-RBC autoantibody has considerably improved our understanding of the B-cell responses involved in AHA, although our knowledge of T-cell immunity in AHA is still limited. The identification of the major T-cell epitope in the context of MHC class II molecules would be of paramount importance in helping to elucidate the cellular and molecular basis central to the development of AHA.