Although modifier genes are extensively studied in various diseases, little is known about modifier genes that regulate autoimmune diseases. Autoimmune disease caused by the Fas(lpr) mutation depends on the genetic background of mouse strains, suggesting a crucial role of modifier genes. MRL/MpJ-Fas(lpr) (MRL/lpr) and AKR/lpr mice develop severe and mild lupus-like autoimmune disease, respectively, whereas this mutation does not cause disease on C57BL/6 (B6) or C3H background. Both MRL and AKR carry the same haplotype of the Cd72 gene encoding an inhibitory BCR coreceptor (CD72(c)), and CD72(c) contains several amino acid substitutions and a deletion in the extracellular region compared with CD72(a) and CD72(b). To address the role of Cd72(c) locus in the regulation of Fas(lpr)-induced autoimmune disease, we generated B6.CD72(c)/lpr and MRL.CD72(b)/lpr congenic mice. Introduction of the chromosomal interval containing Cd72(c) did not cause disease in B6 mice by itself, but caused development of lupus-like disease in the presence of Fas(lpr) on B6 background, clearly demonstrating that this interval contains the modifier gene that regulates Fas(lpr)-induced autoimmune disease. Conversely, MRL.CD72(b)/lpr congenic mice showed milder disease compared with MRL/lpr mice. We further demonstrated that Cd72(c) is a hypofunctional allele in BCR signal inhibition and that CD72 deficiency induces severe autoimmune disease in the presence of Fas(lpr). These results strongly suggest that the Cd72(c) is a crucial modifier gene that regulates Fas(lpr)-induced autoimmune disease due to its reduced activity of B cell signal regulation.