The study of NZB x C58 recombinant inbred mouse strains has revealed independent segregation of naturally occurring thymocytotoxic antibody and Coombs' anti-erythrocyte autoantibody. The lack of concordance of either of these autoantibodies with known heavy and light chain markers suggests that the autoantibodies are produced as a result of regulatory gene defects rather than alterations of antibody structural genes. Further, lack of concordance of the various autoimmune traits with each other or with H-2 or virus expression suggests that the autoimmune phenotype is not the result of a single "autoimmunity' gene but rather the outcome of faulty regulation of a number of independently segregating genes.