A modification of the enzyme-linked immunosorbent assay (ELISA) is described, that permits determination of antibodies to native DNA (nDNA). The same approach can be used to measure antibodies to denatured DNA (dDNA). Poor binding of nDNA to the polystyrene solid phase has presented difficulties in using the ELISA method for assaying anti-nDNA activity (Engvall, 1976), but we find that precoating of the solid phase with protamine sulfate circumvents this problem. Assays for anti-dDNA are also enhanced by the use of protamine sulfate coated tubes. We have used the ELISA method to assay 15 SLE and 27 non-SLE sera for anti-nDNA and anti-dDNA activity. The results are compared with those obtained using the GF/A glass fiber filter assay, previously described by Lewis et al. (1973).