HLA phenotypes were determined in 60 Caucasoid patients with rheumatoid arthritis (RA) and normal serum antibody levels to native type II collagen. Antigen frequencies were compared with 52 patients with RA who had elevated antibody levels to native type II collagen. Both RA groups were compared with 163 healthy controls. A clinical comparison of both RA groups yielded few differences, except a decreased incidence of rheumatoid factor and a positive family history of RA and radiologically, increased osteosclerosis in the RA group with elevated antibodies to native type II collagen. HLA-DR4 was increased and HLA-DR7 was decreased in the RA group with normal antibody levels to native type II collagen. A comparison of both RA groups showed an increased incidence of HLA-DR4 in the normal antibody group, whereas HLA-DR7 was increased in the elevated antibody group. In the elevated antibody group the majority of patients possessed either HLA-DR3 or DR7 both of which are in strong linkage disequilibrium with HLA-DQw2. This immunogenetic data suggests that RA patients with autoimmunity to native II collagen form a distinct genetic subset of RA.