The relationship between clinical activity of systemic lupus erythematosus (SLE) and molecular sizes of DNA fragments isolated from DNA/anti-DNA antibody immune complexes were examined. Among sera from twenty-eight patients with SLE examined, three different molecular sizes of DNA were identified, namely, DNA of m.v. 25,000 with 30 to 50 base pairs (bp); m.w. 100,000 with 150 to 200 bp; and m.w. 200,000 with 300 bp. On the basis of the molecular sizes of DNA fragments, we can divide patients with SLE into four groups. The first group contained DNA predominantly of m.w. 25,000. The second group contained DNA predominantly of m.w. 100,000. The third group contained DNA of m.w. 200,000. The fourth group contained both m.w. 25,000 and 100,000. A method to quantitate the amounts of DNA in DNA/anti-DNA immune complexes was developed. The amount of DNA fragments was estimated by measuring the amount of 32P-phosphate incorporated into 5 ends of DNA. Patients with severe disease tended to have greater amounts of DNA (up to 400 ng/ml serum). Two serial studies also support this result. Thus, the quantitative analysis shows that the amount of DNA in the immune complexes is highly correlated with disease activity (r = 0.864; p less than 0.001). These results suggest that DNA/anti-DNA immune complexes may play some role in the pathogenesis of lupus nephritis.