Warm autoimmune hemolytic anemia (WAIHA) is characterized by an accelerated extravascular clearance of red blood cells (RBC) mediated by RBC-bound IgG autoantibodies. We have recently demonstrated significantly altered self-reactive antibody (Ab) repertoires of plasma IgM in WAIHA patients. The natural IgM Ab repertoire in plasma is critical in modulating both autoimmune and alloimmune responses. In the present study, we investigated IgM and IgG Ab repertoires of WAIHA patients toward nonself antigens (Ag) using a quantitative immunoblotting technique, followed by multiparametric statistical analysis of the data. We demonstrate significantly altered Ab repertoires of IgM and IgG toward nonself Ag in WAIHA patients. The reactivity of plasma IgM of WAIHA patients was reduced compared to that of healthy individuals, independent of administering an immunosuppressive therapy. We observed that an increase in reactivity of plasma IgM during clinical remission of the disease was associated with the development of allo-Ab toward RBC-antigens during RBC transfusions. Taken together, the data indicate altered Ab repertoires of plasma IgM and IgG toward nonself Ag in WAIHA patients. A broadly reduced reactivity of plasma IgM toward nonself Ag might influence the adaptive immune response in WAIHA patients.