NZB x NZW (NZB x W) F1 hybrid mice spontaneously develop a disease most prominently characterized by immune complex glomerulonephritis (GN), which seems to be associated with both antibodies to DNA and to the serum retroviral envelope glycoprotein, gp70. To evaluate the contribution of each of these autoimmune responses to the pathogenesis of the GN, we studied NZB x W F2 mice in which the two responses appeared to segregate relatively independently. Use of this model permitted analysis of possible correlations between each response and the G.N. The presence of circulating anti-gp 70-complexed gp70 correlated significantly with the development of fatal GN and one could predict the course of renal disease by computing the rising serum levels of gp70 complexed with antibodies. In contrast, the presence of free antibodies to either double-stranded or single-stranded DNA was not significantly associated with the development of fatal GN. This association of anti-gp70 antibody production with these animals' early death from GN strongly suggests that the gene(s) governing production of antibodies to serum retroviral gp70 may be one of the major genes responsible for spontaneous renal disease segregated in NZB x W F2 generations.