The glomerulonephritis in systemic lupus erythematosus (SLE) is presumably triggered by the binding of circulating immune elements (autoantibodies and immune complexes) to the glomerulus; however, the nature of these elements is unclear. In order to detect and characterize such elements, we developed an ELISA using whole intact glomeruli as the substrate. With this assay, glomerular binding activity (GBA) was detected in the serum of MRL lpr, NZB x W, and B x SB mice, but not in non-autoimmune BALB/c mice. Less activity was present in the serum of C3H lpr, C57Bl/6J lpr and AKR lpr animals which develop signs of autoimmunity but only modest renal disease. The GBA in MRL lpr mice contained IgG (subclasses 1, 2a and 2b), but not IgG3, IgM, IgA, or C3. GBA was not significantly decreased by preadsorption of MRL lpr serum by DNA-agarose (although anti-DNA antibodies were). Binding activity in serum, however, was diminished by DNAase treatment. Fractionation of MRL lpr serum over a molecular sizing column showed that GBA eluted in a broad peak. GBA bound to the glomerulus ex vivo in a tissue-specific fashion and was enriched in renal eluates relative to serum in vivo. In sum, the binding activity detected by this assay appeared to be a heterogeneous entity (possibly in part immune complexes containing DNA) which bound specifically to the glomerulus and which appeared to parallel the presence of renal disease. This novel assay system may help elucidate the pathogenesis of SLE nephritis and have utility as a disease marker.