Although autoantibody activities are rather often associated to monoclonal gammopathies, only monoclonal immunoglobulins of the IgM isotype are really directed against autoantigens that are often polysaccharides or are formed by highly repetitive structures. This strict association is frequently revealed also by clinical manifestations of the autoimmune response generated by the monoclonal macroglobulin. Most monoclonal immunoglobulins of non-IgM isotype are instead totally inactive toward self-antigens, the autoantibody activity being instead associated, if present, to polyclonal immunoglobulins. Although the same BAFF/APRIL system is involved in perpetuation of humoral autoimmunity as well as in stimulation of clonal B-cell expansion, the autoimmune commitment of B cells of a non-IgM isotype is hardly compatible with their possible involvement in an uncontrolled proliferation pathway, whose prerequisite is the homing of these B cells to the bone marrow compartment. The IgM-secreting cells appear instead to possess a much lower tendency, and/or a looser requirement, for their homing in the bone marrow prior to their actual proliferation. This may explain the quite different consequences, in terms of autoimmunity, between IgM and non-IgM paraproteinemias.