The occurrence of early severe lupus nephritis in (NZB x NZW)F1 mice must depend on the action of at least two dominant or codominant genes (at least one gene from each parent) as neither of the inbred parental strains shows the disorder. Identifying affected animals by antemortem determinations of renal function, we have studied the incidence of the renal disease in 230 (NZB x NZW) x NZW backcross mice (an earlier study) and, in this study, in 150 (NZB x NZW) x NZB backcross mice. The data indicate that the NZB strain contributes only one gene and the NZW strain contributes two genes, or clusters of closely linked genes, to the renal disorder of the F1 hybrid. One of the NZW genes was found to be linked to the H-2 complex. All three genes must be dominant or codominant, as their effect is expressed in the heterozygous state.