Natural autoantibodies play an important regulatory role in the maintenance of immune homeostasis. They act as a first line of defense against environmental pathogens like toxins, bacteria and erythrocytes. In humans they are mainly produced by CD5+ B cells that are under the control of a regulatory T cell population. Fc-gamma receptors are involved in antigen recognition and signal transduction and tuning, and some of the members of the FcR family have structural similarity to MHC molecules; they may interact with multiple Ig ligands and with non-Ig ligands. We discuss the interactions between immune-complexes formed with natural autoantibodies and Fc-gamma receptors and suggest that such interactions may affect self-recognition in the thymus and regulate immune homeostasis.