The HLA-D region in the HLA chromosomal complex is concerned with cellular interactions and regulation of the immune response. Rheumatoid arthritis (RA) has been found to be associated with one of the HLA-D antigens. In two separate studies from this laboratory it was found that HLA-Dw4 was more frequent in RA patients than in normal controls. The patients were Caucasians suffering from erosive, rheumatoid factor positive RA. Combined results of the two studies showed HLA-Dw4 to be present in 52% of the 130 patients, compared to 13% in 119 controls (P less than 10(-6). Ia antigens were determined serologically in isolated B cells. The antigen Ia4, associated with HLA-Dw4, was increased in RA patients (70%), compared to normal controls (28%). In SLE, typing was difficult because of fragility of the B cells. Preliminary results in 14 SLE patients suggested that Ia4 was also increased in this disease. It seems likely that these associations are a reflection of genetic factors related to the immune response involved in the pathogenesis of RA and perhaps also of SLE.