Serologic HLA typing was performed in 77 patients with juvenile arthritis (JA). The frequency of the DR4 antigen was significantly increased in the seropositive but decreased in the seronegative patients—53% and 17%, respectively (P < 0.025)—compared with 27% in healthy Norwegians. An increased frequency of the HLA-DR4 antigens was also found in polyarticular onset JA (50% compared with 27%, P < 0.05). The frequency of both the HLA-B27 (21%) and the DR5 antigen (21%) was increased in the whole patient group compared with controls (10% and 9%, respectively, P < 0.01). The DR5 antigen was also increased in the systemic onset patients (40%, P < 0.05). Both the DR5 and the DR8 antigens were increased in the pauciarticular onset group (P < 0.05 and P < 0.01, respectively). The results support the view that seropositive and seronegative JA are different disease entities and also that seropositive JA may be an early form of seropositive rheumatoid arthritis. The association between the DR4 antigen and IgM rheumatoid factor suggests that the HLA-DR4 gene or a closely linked gene may regulate autoimmune responses to self IgG.