Using DNA techniques, we investigated the role of HLA-DR, DQ, and DP alleles in susceptibility to juvenile arthritis (JA). We studied 2 groups of patients with JA having a different disease prognosis and course. The pauciarticular form is usually benign, while the polyarticular disease frequently leads to joint destruction and disability. Persistent pauciarticular disease developed preferentially in patients having HLA-DRw13-Dw18 and DQw6-Dw18, but these antigens did not confer susceptibility in patients whose disease converted to the polyarticular form. HLA-DPw2.1 was an additional susceptibility factor for patients with JA of pauciarticular onset. In the polyarticular form of JA, HLA-DPw3 was the major factor for susceptibility, giving a relative risk of 10.3 (P less than 0.0001). In addition, we found that DRw8.1 and DQw4 were increased, and HLA-DR4 was markedly decreased, in patients with pauciarticular and polyarticular disease. These results indicate that in addition to some shared factors, distinct HLA class II alleles are important in pauciarticular or polyarticular JA. We conclude that typing with oligonucleotide probes may be useful in predicting the outcome in some children with arthritis.