In the present study, we mapped the major quantitative trait loci (QTL) differing between the NZW and C57BL / 6 inbred strains of mice by making use of (NZW × C57BL / 6.Yaa)F1 mice, a model in which the lupus‐like autoimmune syndrome observed in male mice is associated with the presence of an as yet unidentified Y chromosome‐linked autoimmune acceleration gene, Yaa. Linkage analysis of 126 C57BL / 6 × (NZW × C57BL / 6.Yaa)F1 backcross males provided evidence for a major QTL on chromosome 7 controlling both the severity of glomerulonephritis and the production of IgG anti‐DNA autoantibody and retroviral gp70‐anti‐gp70 immune complexes. Two additional QTL of C57BL / 6 origin on chromosome 17 had no apparent individual effects, but showed strong epistatic interaction with chromosome 7 QTL for disease severity and anti‐DNA autoantibody production. Our data also identified on chromosome 13 a QTL of NZW origin with a major effect on the level of gp70, and showing an additive effect with the chromosome 7 QTL on the level of gp70 immune complexes. Our study thus provides a model to dissect the complex genetic interactions that result in manifestations of murine lupus‐like disease.