Because DNA polymorphisms of immunoglobulin kappa confer risk for rheumatoid arthritis (RA) and not all persons with RA have the HLA-DR4 marker, genomic polymorphisms of immunoglobulin kappa and HLA-DR beta were determined in white patients with RA. Compared with control subjects matched for DR beta genotype, the homozygous genotype of the constant segment of immunoglobulin kappa (C kappa) was more frequent in the subgroups of RA patients without the DR beta genotype corresponding to HLA-DR4 (relative risk 6.2, P less than 0.01) and patients without DR4 or DR1 (relative risk 6.7, P = 0.013), but not in the DR4+ RA subgroup. Therefore, RA may be a genetically heterogeneous disease, with HLA-DR4 marking one genetic subset and the homozygous C kappa genotype marking another.