Seropositive rheumatoid arthritis is genetically linked to a group of HLA-DRB1 alleles sharing a sequence motif within the third hypervariable region. Controversy exists over the role of the distinct allelic variants in affecting not only the risk to develop disease, but also in modifying the expression of the disease. We have stratified 81 patients according to their patterns of disease manifestations and identified the HLA-DRB1 alleles by polymerase chain reaction amplification and subsequent oligonucleotide hybridization. To identify precisely the allelic combinations at the HLA-DRB1 locus, homozygosity was confirmed by locus-specific cDNA amplification and subsequent sequencing. Our study demonstrated a high correlation of allelic combinations of disease-associated HLA-DRB1 alleles with the clinical manifestations. Characteristic genotypes were identified for patients who had progressed toward nodular disease and patients who had developed major organ involvement. Rheumatoid nodules were highly associated with a heterozygosity for two disease associated HLA-DRB1 alleles. Homozygosity for the HLA-DRB1*0401 allele was a characteristic finding for RA patients with major organ involvement. Our data suggest a role of the disease-associated sequence motif in determining severity of the disease. The finding of a codominant function of HLA-DRB1 alleles suggests that the biological function of HLA-DR molecules in thymic selection might be important in the pathogenesis of RA.