Objective: To evaluate the relation between the presence of the 'rheumatoid epitope,' defined by a sequence motif in the HLA-DRB1 alleles, and disease severity in African-American patients with rheumatoid arthritis. Design: Cross-sectional study. Setting: Rheumatology outpatient clinics at two university medical centers. Patients: 86 African-American patients with rheumatoid arthritis (66 seropositive and 20 seronegative for the rheumatoid factor) attending the clinics and 88 healthy African-American persons. Measurements: HLA-DRB1 alleles were determined by restriction fragment length polymorphism and by allele-specific oligonucleotide typing of polymerase chain reaction-amplified HLA-DRB1 second exons. Results: With the exception of an increased frequency of HLA-DRB1*04 alleles in seropositive patients with rheumatoid arthritis (27.3%) compared with controls (13.1%) (P = 0.02), the frequencies of HLA-DRB1 alleles were similar in patients and controls. Most seropositive (48 of 66) and seronegative (15 of 20) patients were HLA- DR4 negative, but some (7 of 48 seropositive patients and 3 of 15 seronegative persons) inherited the rheumatoid epitope on a non-DR4 allele. Disease features, including severity, were similar for patients without the epitope and for those with either a single or a double dose of an epitope- positive allele. Positivity for rheumatoid factor, but not for the rheumatoid epitope, was weakly associated with severity in these patients. Conclusion: Most African-American patients with rheumatoid arthritis did not express the rheumatoid epitope. The predisposition to and severity of rheumatoid arthritis in African-Americans appears to be independent of the presence and dose of the shared rheumatoid epitope.