Despite many reports on the association between ankylosing spondylitis and HLA-B27, most studies have failed to find a significant relationship between HLA-A or B antigen and rheumatoid arthritis. Stastny, however, showed a significantly high frequency of HLA-Dw4 in rheumatoid arthritis in 1976. The study of HLA antigens in Japanese patients with rheumatoid arthritis are thought to be significant in view of the pathogenesis of disease. Eighty-eight Japanese patients with "definite" or " classical" rheumatoid arthritis according to the ARA criteria and 104 normal individuals were typed for serologically detectable HLA-A, B, C, and D antigens. Though small discrepancies were observed in several of the HLA-A, B, and C, antigens, they were not definitely significant. The frequency of HLA-DR4 increased to 70.5% in patients compared to 46.1% in the control (i.e. normal) group (p less than 0.001). However, the frequency increased to 80.6% in male patients (p less than 0.0005). Of interest was the significantly high frequency of HLA-DR4 in males, compared to the low frequency of HLA-DR2 (p less than 0.02). Rheumatoid patients were subdivided into different groups according to the year of onset, the presence of the the rheumatoid factor or rheumatoid nodules, the functional grade and treatment. There were no significant differences in the frequency of HLA-DR4 among subgroups. The results indicate that rheumatoid arthritis, especially in males, is associated with genes of the HLA-D region and that immunogenetic factors linked to HLA have an important role in its pathogenesis.