An enzyme immunoassay to detect complement-fixing antibodies to DNA (CF-antiDNA) was developed. Of SLE sera, 64% had these antibodies as did 6% of 50 rheumatoid arthritis and 3.2% of 93 normal human sera. The mean CF-antiDNA level was higher in the sera of SLE patients with renal disease than those SLE patients who had no renal disease (P less than 0.0001), and higher in those SLE patients with active rather than inactive renal disease (P = 0.006). CF-antiDNA was more closely associated with renal activity than total IgG-antiDNA or CH50. These observations suggest that both the quality and quantity of anti-DNA antibodies play a role in the pathogenesis of renal disease, and that modern enzyme immunoassays help distinguish the relative importance of complement-fixing antibodies to anti-DNA from that of total anti-DNA.