BAFF blockade is efficacious in murine and human SLE. Whereas the attendant reduction in B cells contributes to the efficacy, it remains unresolved whether a B cell-independent component also contributes. Since accurate assessment of a B cell-independent component can only be made in a B cell-independent autoimmune disease, we investigated MOG35-55-induced EAE in C57BL/6 mice. Neither pharmacologic neutralization nor genetic elimination of BAFF affected disease, nor did elimination of APRIL (with or without elimination of BAFF) or constitutive over-expression of BAFF. Eliminating BAFF had no effect on disease even in mice that were genetically manipulated to maintain greater-than-normal numbers of B cells. However, elimination of BAFF in B cell-deficient mice dramatically reduced disease, thereby unmasking a B cell-independent contribution of BAFF to an autoimmune disease. Our findings raise the plausibility that BAFF contributes to SLE not only through effects on B cells but through B cell-independent pathways as well.