G(IX) congeneic mouse strains, C57BL/6-G(IX) (+)(B6-G(IX) (+)) and 129-G(IX) (-), have been derived from the prototype strains, B6(G(IX) (-)) and 129(G(IX) (+)). The hybrids, (B6-G(IX) (+) x 129)F(1) (G(IX) (+)F(1)) and (B6 x 129-G(IX) (-))F(1) (G(IX) (-)F(1)), differ only in regard to genetic loci controlling G(IX) antigen expression. G(IX) (+)F(1) mice spontaneously produce G(IX) antibody and often show signs of autoimmune disease and lymphoproliferative disease. G(IX) (-)F(1) mice and mice of the two parental strains (B6-G(IX) (+) and 129) of G(IX) (+)F(1) do not produce G(IX) antibody and seldom show signs of these diseases. G((ERLD)), and G((RADA1)), antibodies, natural thymocytotoxic autoantibody, and antinuclear antibodies were produced by G(IX) (+)F(1) mice. However, these four antibodies were also found in the other strains. G(IX) (+)F(1) mice develop pronounced diffuse glomerulonephritis similar to that found in systemic lupus erythematosus in man. Incidence studies in which mice were examined according to age rather than state of health showed that the lesions occurred in 38% of G(IX) (+)F(1) mice but not in G(IX) (-)F(1), B6-G(IX) (+), or 129 mice. Lymphoproliferative lesions were either reticulum cell sarcoma (RCS) type A or reactive lymphoid hyperplasia (RLH). RCS occurred more often in G(IX) (+)F(1) (38%) than in G(IX) (-)F(1) (12%) or B6-G(IX) (+) (8%). No RCS occurred in mice of the 129 strain. RLH occurred in G(IX) (+)F(1) mice (10%) but not in the other strains. From these results, the following conclusions are drawn: (i) Severe glomerulonephritis and the increased occurrence of lymphoproliferative lesions in these animals depend on the presence of G(IX) antigen; (ii) besides genes controlling G(IX) antigen expression, other genes from both parental strains are required to create the basis in the progeny F(1) mice for the development of these diseases; and (iii) the chronic production of G(IX) antibody may be necessary for the development of the severe glomerulonephritis and for the increased occurrence of lymphoproliferative diseases in G(IX) (+)F(1) mice.