Both genetic and environmental factors, including infection by pathogens, affect the development of autoimmune diseases such as lupus. We are investigating the effect of viral infections on the lupus model of FcγR2B-/- mice. We infected FcγR2B-/- mice a single time at 2 months of age with vesicular stomatitis virus (VSV) and observed the development of autoimmune disease for the following 6 months. Infection with VSV significantly reduced autoantibody titers in serum and improved survival of FcγR2B-/- mice. B cell development in the bone marrow was not affected in VSV infected mice whereas memory B cells, and germinal center, plasma, and IgG producing mature B cell numbers were reduced. VSV infected FcγR2B-/- mice had lower number of follicular helper T cells and CD11c+ cells in the spleen. Increased survival in these mice correlated with a reduction of inflammatory cytokines and chemokines in the serum. The fact that a single round of infection with VSV confers long time protection from lupus in this mouse model indicates that the suppressor mechanism underlying the VSV effect on autoimmunity could be an excellent candidate for therapies seeking long term efficacy.